med neuro mod 1 notes

Yong Lu, Ph.D, Neurons and Glia, MN

Neurons and Glia Learning Objectives 1. Describe the microanatomy of a typical or stylized neuron and all of its parts and processes. What is special about neurons compared to other cells?

2. Describe the general functions of each part of a neuron in information processing.

What enable neurons to receive, process, and transmit information?

3. Define the three major types of neurons and their locations; also the major variations among multipolar neurons and their locations.

4. Describe the types of axonal transport and their function.

5. List the differences between glia and neurons.

6. Describe the major types of supporting cells in the PNS and CNS and their functions.

7. Describe the differences in terms of myelination between CNS and PNS. What is the function of myelin? Describe the consequences of disruption of myelin.

8. Tumors of the nervous system originate from cell types that retain their potential to proliferate. Based on your knowledge of the cell types that compose the nervous system, which cell types would you expect to be likely to give rise to tumors?

9. Define the following terms and identify these structures in appropriate images: axoplasm multipolar bipolar pseudounipolar presynaptic membrane postsynaptic membrane synaptic cleft node of Ranvier myelinated unmyelinated anterograde transport retrograde transport dendritic spine neurotransmitter axon dendrite axon hillock Schwann cell Nissl substance myelin synapse Purkinje cell synaptic vesicles pyramidal cell microtubule neurofilament astrocyte oligodendrocyte microglia

Reading assignment: Purves Chapter 1, pp 2-10 Answers to the practice questions at the end of this lecture note: Answers 1. A 9. A 2. A 10. B 3. B 11. A 4. A 12. B 5. A 13. A 6. A 14. A 7. B 15. E 8. A 1

Yong Lu, Ph.D, Neurons and Glia, MN

References and Image Acknowledgments: References used in Lu’s eight lectures (Neurons and glia, Synaptic transmission I, II, III, Synaptic Integration, Development of the nervous system, Circuit formation, Repair and Regeneration) are listed below. The use of specific images is individually acknowledged in both the lecture notes and Powerpoint presentations.

Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, Mooney RD, Platt ML, White LE (2018) Neuroscience. 6th ed., Oxford University Press.

Felten DL, Józefowicz RF (2003) Netter’s Atlas of Human Neuroscience. 1st ed., Icon Learning Systems.

Squire LR, Bloom FE, McConnell SK, Roberts JL, Spitzer NC, Zigmond MJ (2003). Fundamental Neuroscience. 2nd ed., Academic Press.

Access Medicine from McGraw-Hill, http://www.accessmedicine.com Additional images by Yong Lu, Ph.D.

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Yong Lu, Ph.D, Neurons and Glia, MN

I. Overview Two cell types in nerve tissue: neurons and glia 1. neuron (nerve cell): the information processing cell in the nervous system (NS) 2. glia (neuroglia): the support (accessory, non-neuronal) cell in the NS II. Neuron (nerve cell) Neurons are compartmentalized (having several specialized parts).

Components: -Soma (cell body, perikaryon): central region of the neuron containing the nucleus -axon: a neurite (a thin tube extending from a neuronal cell body) specialized to conduct nerve pulses (carries electrical information away from the soma) -dendrite: a neurite specialized to receive inputs from other neurons (carries electrical information toward the soma and the axon) -axonal terminal: site of transmission of information & point of communication Many drugs or toxins can influence the function of the axon or synapse (e.g., block conduction, transmitter release or transmitter reuptake). You’ll learn more about this in my future lectures on synaptic transmission.

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Yong Lu, Ph.D, Neurons and Glia, MN

Neuronal soma (cell body) The soma of a neuron is the metabolic center. Just like other cells, neurons have all kinds of subcellular organelles to achieve various cellular functions (protein synthesis, metabolic maintenance etc.). The nucleus contains genetic materials. Mitochondria are the energy factories, generating biological energy for cellular events. There are lots of mitochondria in neurons; the NS is the greatest consumer of oxygen and glucose. The Golgi complex participates in trafficking and production of cellular materials needed for survival and other functions.

Neurons, as specialized cells, do have specialized cellular components that distinguish them from other types of cells. Neurons make and use special ion channels, which are pore proteins essential for communication between neurons as well as for processing electrical information received from other cells (another type of cells that make and use a lot of ion channels are the muscle cells). Neurons in different regions of the NS make different sets of ion channels to suit their particular functions. Rough endoplasmic reticulum (endoplasmic reticulum + ribosomes; rER) is abundant in the neuronal cytoplasm, and can be stained well by a technique called Nissl staining and the stained patches are called Nissl body (Nissl substance). Observation of Nissl body is unique to neurons.

In addition, due to high metabolic activity of neurons, a byproduct called lipofuscin (yellowbrown pigment granule) can be seen in cell bodies. If accumulated too much, lipofuscin can damage neurons, causing neuronal degeneration.

Neuroscience Fig 1.6

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 4.1 Nissl body

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Yong Lu, Ph.D, Neurons and Glia, MN

Axon Among all kinds of cells, only neurons have structures called axons. Each neuron has only one axon, a relatively long process (a few mm to >1 m in length) with uniform diameter. An axon has few branches along most of its length, and forms branches extensively near the distal site where synaptic connections with other cells occur. Microtubules (a polymer of the protein tubulin, forming a straight, hollow tube 20 nm in diameter. A component of the cytoskeleton), and neurofilaments (a type of intermediate filament found only in neurons, Type-IV intermediate filament, 10 nm in diameter; an important component of the neuronal cytoskeleton) run along inside the axon, providing the “skeleton” to support the structure of an axon. Microtubules are the “highway” in an axon, transporting materials in both directions. For such energy-consuming movements to occur, surely there are lots of mitochondria inside the axoplasma (cytoplasm of the axon). There are not many other organelles in axons. There are no ribosomes in most axons (this distinguishes an axon from a dendrite), so little or no protein synthesis occurs in axons. Nearly all proteins needed for the axon to function come from the cell body.

Axons conduct electrical impulses very effectively, just like the way a metal wire conducts electricity. What makes an axon a good biological conductor for bioelectricity? The axoplasma contains intracellular fluid rich of ions such as K+. This confers the axoplasma low resistance for bioelectrical current to flow (a good conductor).

What’s more important for an axon being a good conductor is what‘s outside of an axon, the myelin. We’ll learn more about myelin in this lecture, and in future lectures when we study generation and conduction of nerve pulses (action potentials).

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Yong Lu, Ph.D, Neurons and Glia, MN

Axoplasmic transport Anterograde (orthograde)– – transport materials from the cell body toward the axonal terminals; uses a protein called kinesin (an ATPase, adenosine triphosphatase, which breaks down ATP and produces energy); guided by microtubules, to transport 1) Neurotrophic factors to the targets of the neuron (e.g., muscle cells, or other neurons) 2) Proteins (e.g., ion channels, enzymes) essential for synapses to function 3) Synaptic vesicles (may or may not contain transmitter molecules) 4) Materials for regeneration of axons (e.g., tubulin, actin, etc).

Fast anterograde transport: 100-400 mm/day; proteins in secretory vesicles (these are not synaptic vesicles), neurotransmitters (e.g. peptides) in synaptic vesicles, mitochondria.

Slow anterograde transport: 1 mm/day; cytoskeleton proteins, proteins for regeneration of injured axons, and enzymes involved in producing neurotransmitters.

Retrograde – uses a protein called dynein (another ATPase) with microtubules. Fast: 20-250 mm/day.

1) Growth factors for neuron (e.g., nerve growth factors secreted by muscle cells, picked up by nerve terminals) 2) recycling of components of the axon terminal; macromolecules in vesicles, “old” mitochondria (back to cell body for degradation).

Some viruses can exert their infection of the CNS through retrograde transport (e.g. the rabies virus). Axonal transport is also used as a research tool in studying connections between cells.

Materials to be transported are enclosed within vesicles, which “walk down/up” the microtubules of the axon, using the “legs” provided by kinesin/dynein, and at the expense of ATP. In long axons, transportation of materials back and forth is really a tremendous task, and huge amount of biological energy is needed.

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Yong Lu, Ph.D, Neurons and Glia, MN

Dendrites Dendrites in most cells are very extensive, forming a dendritic tree. Some dendrites have spines (bud-like extension of the dendrite membrane); others don’t. Synapses generally form onto spines. Spines increase the area of a neuron forming communication sites with others.

Spines are also relatively independent, both biochemically and electrically (input on one spine does not affect input on another spine); this enhances the ability of a neuron in information integration (computing the combined effects of many inputs).

Like axons, dendrites have rich cytoskeleton components such as microtubules and neurofilaments. Mitochondria are present in dendrites. Unlike axons, dendrites contain ribosomes. Therefore, proteins can be made locally in dendrites. This reduces (but does not replace, see food for thought below) the need for transporting many materials from the soma to dendrites, and also fastens the insertion of membrane proteins (e.g. ion channels need to be inserted into the membrane to be functional), which occurs under normal physiological conditions for protein turnover and for neuronal plasticity (changes in neural function). The most important difference between dendrites and axons is probably the presence of lots synapses on dendrites, but few on axons (if any, mostly on the axonal terminals).

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Yong Lu, Ph.D, Neurons and Glia, MN

Food for thought: dendritic transport There is extensive description about axonal transport in various neuroscience texts, but little/none on dendritic transport. One simple reason is that the volume ratio of dendrites:cell body:axon is about on average 5:1:2000, so axonal transport is critical and prominent in axons given their huge volume relative to the dendrites and also due to the lack of protein synthesis in axons. Having said that, dendritic transport is also very important for neuronal functions, and the process is more complicated than that in axons. Keep these points in mind: 1) like in axons, both kinesin and dynein superfamily proteins are involved in dendritic transport; 2) microtubules in axons are oriented uniformly plus end-distal (plus end at the distal part of the axon, and minus end at the proximal part). Kinesin transports materials toward the distal part (anterograde), whereas dynein does the opposite (retrograde); 3) microtubules in dendrites are mixed in orientation. Therefore, transport by the same type of proteins in dendrites could be mixed, too; and 4) the terms of anterograde and retrograde are commonly used for axonal transport, but they apply for dendritic transport too (anterograde is away from the cell body, and retrograde towards the cell body).

Synapses Synapse: the site at which an axon terminal communicates with a second neuron, or with an effector tissue (e.g. muscle). The most common type of CNS synapse is the chemical synapse forming between axon and dendrites, comprising an axon terminal of one neuron that is apposed to a dendrite or dendritic spine of a second neuron. A typical chemical synapse consists of a presynaptic element, a postsynaptic element, and the space between them (synaptic cleft, 20-50 nm). Synaptic vesicles residing in the presynaptic element (axonal terminal) contain high concentration of neurotransmitters (mM range). Receptors of neurotransmitters exist primarily on postsynaptic membrane.

Synaptic vesicles of 3 types: small clear, small dense-core, large dense-core (for neuropeptides). Vesicles contain neurotransmitters of several types: a. amines: acetylcholine, noradrenaline (norepinephrine), adrenaline (epinephrine), dopamine, serotonin (5-hydroxytryptamine, 5-HT). b. amino acids: glutamate, Îł-amino-butyric acid (GABA), glycine. c. peptides: substance P, calcitonin gene-related peptide, enkephalin, endorphin, somatostatin, galanin etc.

What’s special about neurons? polarized & compartmentalized can fire action potentials (not exclusively, muscle cells can too) signal transmission through synapses, especially chemical transmission unique proteins (e.g. ion channels)

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Yong Lu, Ph.D, Neurons and Glia, MN

Types of neurons 1. Bipolar – associated with special senses: retina, olfactory epithelium, auditory & vestibular systems. Have one axon and one dendrite emanating from each end of the soma. Relay sensory information.

2. Pseudounipolar – associated with primary sensory systems: dorsal root & cranial nerve ganglia. They have one process that bifurcates into a central axon and a peripheral axon. The central one enters the CNS (e.g., spinal cord), and the peripheral one extends to the periphery (e.g., skin). The terminal of the peripheral axon functions like a dendrite. Relay information of pain, temperature, touch etc.

3. Multipolar – associated with motor neurons in CNS and autonomic motor neurons in ganglia, interneurons, etc. Have one axon, but many dendrites and are involved in integration and transmission of information. Most common type (>99% of all neurons).

Variations in size & shape & function Purkinje cell – located in the cerebellar cortex. Pyramidal cell – located in the cerebral cortex.

Interneuron – almost everywhere in the NS. Axon Collaterals (to spread influence) and dendritic trees vary according to the functions of neurons. The more inputs a neuron receives, the more extensive its dendritic tree and thus more space for synaptic connections to occur, and the more complex its integrative functions.

Types of neurons: other classifications based on dendrites: pyramidal vs stellate cells; spiny vs aspinous cells based on connections: primary sensory neurons, motor neurons, interneurons based on projection direction: afferent (peripheral toward CNS) vs. efferent neurons based on neurotransmitter: glutamatergic, GABAergic, cholinergic, etc.

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Yong Lu, Ph.D, Neurons and Glia, MN

III. Glia Unlike neurons, glia are generally not involved in receiving, integrating, and transmitting information. Their primary function is control of the environment within the CNS.

Functions of glia in CNS Astrocyte (Astroglia): Star-shaped; protoplasmic astrocytes mainly in gray matter, fibrous (fibrillar) astrocytes (fewer, longer, and slenderer processes) mainly in white matter • provide scaffolding support for neurons • transport nutrients to neurons, secret growth factors • digest parts of dead neurons • regulate content of extracellular space, e.g., pH buffer, reuptake neurotransmitters Microglia: immune effector cells involved in inflammation; digest parts of dead neurons.

Ependymal cells: line ventricles and central canal; produce cerebrospinal fluid.

Oligodendrocyte: Provide the insulation (myelin) to neurons in the CNS. 10

Yong Lu, Ph.D, Neurons and Glia, MN

Myelin in CNS Myelin: a membranous wrapping, or sheath, around axons, provided by oligodendrocytes in the CNS (by Schwann cells in the PNS).

Nerve fibers in the CNS = axon + myelin + oligodendrocyte. The gap between two internodes is called Node of Ranvier. The axon is bare at this point. An axon of a particular neuron is wrapped by myelin formed by many oligodendrocytes.

Most nerve fibers in the CNS are myelinated. Few are unmyelinated.

Differences between glia and neurons: •

non-polarized (no axon; processes are not called dendrites but simply glial processes) • no chemical synapses (do have electrical synapses) • most glia cannot fire action potentials (do have resting membrane potential) • 3 times more in number than neurons • be able to divide after birth (forming brain tumors when proliferation out of control) From Diseases of the Nervous System.

Copyright © 2015 Elsevier Inc.

Clinical note: brain tumors can be formed by over-proliferation of all cell types in the CNS except for neurons.

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Yong Lu, Ph.D, Neurons and Glia, MN

Glia in PNS Satellite Cells: Provide physical support to PNS neurons such as sensory neurons in the dorsal root ganglion (DRG; note that there are no synapses in DRG), postganglionic neurons of the ANS (note that synapses form between the nerve terminals of preganglionic neurons and postganglionic neurons).

Schwann Cells: Provide insulation (myelin) to neurons in the PNS. Nerve fiber (NF) in PNS = Axon + myelin + Schwann cells. Each Schwann cell produces ONE segment of myelin along a part of ONE axon (internode). The gap between two internodes is called Node of Ranvier.

The axon is bare at this point. Most axons of PNS neurons are myelinated; some axons (e.g. axons of some neurons involved in pain sensation, and axons of some postganglionic neurons) are unmyelinated. Unmyelinated axons are merely “buried” in a trough of Schwann cell cytoplasm to protect them from elements in the extracellular space.

One oligodendrocyte produces myelin for several axons. So loss of one oligodendrocyte affects multiple neurons. Thus, loss of one oligodendrocyte could be more damaging to the NS than the loss of one Schwann cell.

CNS

PNS

Netter’s Atlas of Human Neuroscience, Fig I.5

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Yong Lu, Ph.D, Neurons and Glia, MN

Degree (thickness) of myelination. The larger the axon the more myelin around it, and thus, the faster its conduction velocity (the speed impulses travel along the axon to the terminals). Shown below are different types of fibers innervating sensory receptors. axon

myelin

Axon type Diameter (µm) Speed (m/s)

Aa 13-20 80-120

Ab Ad C 6-12 1-5 0.2-1.5 35-75 5-35 0.5-2

Illustrated by Yong Lu, Ph.D.

More on functions of myelin Myelin insulates electrically active axons & increases axonal conduction velocity. Myelin is responsible for “Saltatory Conduction” (dancing or jumping of the electrical impulses) from node to node. The structural basis for this function is the concentrated expression of two types of ion channels in the axon; these channels are the major ones underlying the generation of electrical impulses (action potentials). Voltage-gated sodium channels are strongly expressed (clustered; green in the image) at the center of the Node of Ranvier, whereas voltage-gated potassium channels cluster in paranode (the area close to the node; red in the image) (the structure color in blue is Caspr, contactin-associated protein) (note wrong description in the figure legend on Purves, P8).

Unmyelinated NF: have only a Schwann cell covering to insulate the electrically active axon and provide protection.

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Yong Lu, Ph.D, Neurons and Glia, MN

Clinical note: There are demyelinating diseases of the NS. Demyelination slows down the conduction velocity of electrical impulses because electrical impulses cannot “jump� from one node to the next node; rather they have to travel through the demyelinated axons. This is expressed in the patient as slowness of responses, poor coordination and weakness. An example of this is multiple sclerosis. The image shows myelin loss in the CNS (between horizontal arrows) in multiple sclerosis patient (red: myelin; green: axon and cell body). Another example: Guillain-Barre syndrome (GBS), an autoimmune disease in which antibodies produced by the patient attack myelin formed by Schwann cells in the PNS.

Practice questions: 1. Neurons are polarized because they have axons. A. true ; B. false 2. Compared to other types of cells, neurons have much higher density of mitochondria.

A. true; B. false 3. Nissl body refers to: A. mitochondria B. endoplasmic reticulum and ribosomes 4. Only neurons have axons, and one neuron has only one axon. A. true B. false 5. Nearly all proteins needed in the axon and in axonal terminals are made (being translated) by rERs in the cell body. A. true; B. false 6. Which of the following proteins is used for anterograde axonal transport? A. kinesin; B. dynein 7. Synapses form on dendritic spines, but not on dendritic shafts. A. true; B. false 8. Protein synthesis can occur locally in dendrites.

A. true; B. false 9. Neurons in the dorsal root ganglion are pseudounipolar and sensory. A. true; B. false 10. CNS tumors are formed by over-proliferation of neurons. A. true; B. false 11. Myelin in the CNS is formed by oligodendrocytes. A. true ; B. false 12. The myelin of one particular neuron is formed by either oligodendrocytes or Schwann cells, but not both.

A. true ; B. false 13. The larger the axon, the faster is its conduction velocity. A. true; B. false 14. Voltage-gated Na and K channels are clustered at or around the node of Ranvier. A. true B. false 15. Which statement is true?

A. Ribosomes exist in cell bodies of neurons, but not in dendrites or axons.

B. Only neurons have axons, and one neuron can have multiple axons.

C. Kinesin and dynein are used in retrograde and anterograde axonal transport, respectively.

D. Chemical synapses form on dendritic spines but not on dendritic shafts of neurons.

E. Each Schwann cell produces myelin for only one axon, whereas each oligodendrocyte produces myelin for multiple axons.

Answers: see the first page of the lecture note 14

Orientation to the NS Schofield

ORIENTATION TO THE NERVOUS SYSTEM LEARNING OBJECTIVES Upon mastering this material, the student will be able to: 1. Define anatomical terms as applied to the nervous system.

2. Identify major divisions and related landmarks of the central nervous system.

3. Describe the concept of neural pathways and neuronal circuits as connections of neurons.

4. Describe the concept of a neuronal system.

5. Define “lesion”.

6. Describe conventions regarding image orientation.

7. Associate corticospinal system with voluntary movement, the dorsal column/medial lemniscus system with fine touch, and the anterolateral system with pain.

KEY TERMS afferent anterior anterolateral system brainstem caudal central nervous system central sulcus cerebellum cerebral cortex cerebral hemisphere cerebral peduncle cerebrum contralateral coronal plane corticospinal path decussation diencephalon distal dorsal dorsal column/medial lemniscus

efferent fine touch frontal lobe frontal plane gray matter gyrus horizontal plane hypothalamus inferior insula ipsilateral lateral lateral fissure (sulcus) lesion medial medulla oblongata midbrain nerve nucleus occipital lobe pain

parietal lobe pathway peripheral nervous system pons posterior proximal rostral sagittal plane spinal cord sulcus superior telencephalon temporal lobe thalamus tract ventral voluntary movement white matter

Image Acknowledgments: used, with permission, from: Purves, 6th Edition The Wellcome Collection (http://images.wellcome.ac.uk/) Netter Presenter Image Copyright 2003 Icon Learning Systems. All rights reserved.

Medical Neuroscience AIMS materials (listed as “MN” or “NB Atlas”), copyright NEOMED. Additional images by BRSchofield, 2010-20.

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Orientation to the NS Schofield Outline Anatomical planes Anatomical directions Nervous system subdivisions Central nervous system Peripheral nervous system Central nervous system (CNS) subdivisions Cerebrum Diencephalon Brainstem Midbrain Pons Medulla oblongata Cerebellum Spinal Cord Overview of functions of the major CNS subdivisions Spinal Cord Brainstem Cerebellum Cerebrum Diencephalon Telencephalon Cerebral hemispheres Lobes Insula Neurons and pathways Functional systems and lesions Three main pathways Voluntary motor control: the corticospinal system Two pathways for the sense of touch Fine touch (dorsal column/medial lemniscus, DC/ML) Pain (anterolateral system, ALS) Review Questions Supplemental notes

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Orientation to the NS Schofield

Anatomical directions Medial – lateral medial – toward the midline lateral – away from the midline Proximal - distal proximal - nearer the origin (reference point) distal - farther from the origin (reference point) dorsal - ventral, rostral - caudal, posterior - anterior, superior - inferior: see diagram at right.

Ipsilateral – on the same side Contralateral – on the opposite side Additional terms Decussate – cross the midline (A pathway “decussates”; the region where it does so may be called a “decussation”.)

Anatomical directions and the CNS, as seen in a midsagittal drawing (as if the body were cut down the midline) of the brain and spinal cord.

Image by BRSchofield

file: Anatomical directions and Afferent and Efferent CNS.psd Afferent – “arriving”, i.e., inputs.

Efferent – “exiting”, i.e., outputs.

The terms above can be used to refer to a nucleus or region; for example, inputs to the cerebellum can be referred to as cerebellar afferents. The outgoing fibers, or projections, of the cerebellum could be referred to as cerebellar efferents. So far, pretty straightforward. Confusion can arise when the point of reference is not specified; here, the CNS as a whole is often the reference point. In such a case, “afferent” means sensory, and “efferent” means motor. This will be less confusing after we talk more about sensory and motor systems; for now, remember that afferent and efferent generally mean input and output, respectively, and are referred to a specific point of reference.

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Orientation to the NS Schofield

Nervous system subdivisions • •

central nervous system (CNS): brain and spinal cord peripheral nervous system (PNS): peripheral nerves, autonomic NS (sympathetic and parasympathetic), enteric NS (associated with digestive tract)

insert Purves 1.10 part 1, part 2

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Orientation to the NS Schofield

CNS subdivisions Cerebrum – conscious perception, thought, volition Diencephalon Brainstem – basic life support, hearing, balance Midbrain Pons Medulla oblongata (almost always called simply “medulla”) Cerebellum (non-conscious motor control: aspects of motor control of which we are not consciously aware/do not require conscious thought) Spinal Cord – sensory and motor control, reflexes

Image below is enlargement of the upper left part of image at right.

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Orientation to the NS Schofield

Overview of functions of the major CNS subdivisions Spinal Cord • Connects brain to periphery • Connects with spinal nerves to coordinate many activities o sensation o muscle control o reflexes o autonomic nervous system Brainstem - basic life support, some special senses For example: • cardio-respiratory centers • maintain consciousness • balance, hearing, taste, • sensory and motor of face • also, connects spinal cord with higher centers Medulla oblongata (or simply “medulla”) Pons Midbrain

from Netter, Fig. I.37

Cranial nerves – nerves attached to the brain (so they are not a part of the CNS, they are part of peripheral nervous system). Nerves III-IX and XII are attached to the brainstem.

Note space between the pons and cerebellum. This is the fourth ventricle, part of a series of spaces – the ventricular system –in the brain. These spaces are filled with cerebrospinal fluid. (More in an upcoming lecture.)

M.O. – medulla oblongata. SC – spinal cord MN. file: NB atlas.midsag bs.jpg

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Orientation to the NS Schofield Cerebellum - (non-conscious contributions to motor coordination) The picture shows a posterior view of a brain in which the telencephalon and most of the cerebellum have been removed. The cerebellum connects to the brainstem by 3 pairs of fiber bundles called cerebellar peduncles (peduncle = stalk). In the picture, the cut peduncles can be seen on the left side (labeled scp, mcp, icp). scp – superior cerebellar peduncle mcp – middle cerebellar peduncle icp – inferior cerebellar peduncle

from Netter, Fig I.43A. file:cereb bs dissec labeled.psd

Cerebrum (forebrain): diencephalon + telencephalon Two more stalks of fibers – the cerebral peduncles [not cerebellar] – connect the cerebrum to the brainstem.

Most of the surface of the forebrain is covered by cerebral cortex, which is folded into gyri (the bumps; singular - gyrus) and sulci (the grooves; singular – sulcus).

Diencephalon (“between brain” [between cerebrum and brainstem]) The two largest parts of the diencephalon are: from Netter, Fig. I.26 file: basal tel,no bstem.labels.psd

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Orientation to the NS Schofield

Thalamus (formally called “dorsal thalamus”, but routinely referred to simply as “thalamus”). The thalamus is the “gateway” to cerebral cortex, meaning that information must go through the thalamus to get to the cerebral cortex.

Sensory, motor, other functions.

Hypothalamus MN. file: midsag dien himagoutlines.jpg • master of the autonomics; endocrine systems for homeostasis • powerful association with emotions Cranial nerve II

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Orientation to the NS Schofield Telencephalon – conscious perception, thought, volition, conscious control of movement.

Also known as the cerebrum, comprising two cerebral hemispheres (left and right).

• cerebral cortex (comprising gyri and sulci) on surface • divisible into lobes • beneath the surface: nuclei and white matter • cranial nerve I The cerebral hemispheres. Anterior is to the left. MN. file: hemispheres.jpg Many axons are wrapped in myelin; neuronal cell bodies and their dendrites do not have myelin. In areas where all these elements are mixed, fresh tissue is gray in appearance, and thus called gray matter. In many areas, axons are collected into bundles, or tracts, that have few or no neurons within them. If many of the axons are wrapped with myelin, the area will appear white in fresh tissue, and is called white matter. The figure to the right shows a cut through fresh brain tissue, revealing the internal structure through part of the cerebrum. Here, gray matter provides a covering; white matter is prominent beneath the gray matter covering, and additional (file: fresh brain slab.jpg) Note: clumps of gray matter are evident in the interior. As superior is down; inferior is up in this we will see later, a cut through the spinal cord reveals a different arrangement, where white matter image. forms the bulk of the “outer” regions and gray matter is concentrated internally. The characteristic arrangements will help us to identify different parts of the CNS in various types of images, including fresh or fixed tissue as well as images based on computerized tomography (CT) or magnetic resonance (MRI).

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Orientation to the NS Schofield Lobes of the cerebral hemispheres The cerebral hemispheres can be divided into lobes: frontal lobe parietal lobe occipital lobe temporal lobe Some important sulci form landmarks for lobes Lateral fissure (or sulcus; also known as Sylvian fissure): partially separates temporal lobe from others Central sulcus: separates frontal and parietal lobes.

Parieto-occipital sulcus (on medial surface of hemisphere): separates the parietal and occipital lobes

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Orientation to the NS Schofield There is also an important “island” of cortex that is invisible on the intact brain unless you pry open the lateral fissure. This area of cortex is called the insula, which means “island”. You will get to see this in lab. In the fixed brains, it is difficult to pry open the lateral fissure without damaging the adjacent cortex, so we have removed the cortex overlying the insula in a special dissection so you can see the insula in an otherwise intact hemisphere. Of course, you will get a clear view of the insula when we begin (over the next couple weeks) to look at the hemispheres that have been cut into slabs.

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Orientation to the NS Schofield

Neurons and Pathways

Top: drawings of two representative neurons. Bottom: an example of how each neuron can be drawn schematically. Note the absence of dendrites in the schematic.

Lower image by BRSchofield, file: neurons,schemneuron.jpg

Traditional format for drawing a neural pathway. The left panel shows a generic pathway; the information flow is “upward”; this arrangement is routinely used to represent the flow of sensory information from the receptor to the parts of the brain responsible for perception. Right panel: schematic drawing of a specific sensory pathway, with the midline of the body indicated with a dotted vertical line.

Image by BRSchofield, file: schem2paths.jpg

A pathway consists of a sequence of neurons that are connected by synapses (sites of communication between neurons). In common shorthand, a circle represents a neuron (actually, a group of related neurons, i.e., a nucleus) and a line from that circle represents the axons that form the fiber pathway/tract that travels to the next neuron/nucleus. A single axon can be called a fiber; the collection of axons from one place to another is called a tract (in the periphery, but not in the CNS, a bundle of axons is called a nerve). The bifurcation at the end of the line (axon), adjacent to the next circle, represents a synapse with the next neuron in the circuit. Most neurons have dendrites attached to the cell body. Many synapses often make contact on the dendrites; dendrites are assumed to be present, but not drawn. An important term that we will use frequently when describing circuits is “project” (used as a verb; emphasis on second syllable; the related noun form is “a projection”). In the schematic pathway drawn above right, Nucleus B projects to Nucleus C. This is shorthand for saying, “The neurons whose cell bodies are in nucleus B have axons that extend to Nucleus C and terminate on (i.e., form synapses with) the neurons in Nucleus C. The 12

Orientation to the NS Schofield term “projects” therefore refers to the extension of axons from one nucleus or area to another. Referring again to our schematic pathway, the projection from Nucleus B to Nucleus C is made up of axons that originate from cells in Nucleus B and that travel in Tract 2. It is NOT CORRECT to say that Nucleus A projects to Nucleus C; this statement characterizes the pathway, and describes where information flows, but the term “projects” refers only to the direct target of the nucleus in question; i.e., Nucleus A projects to Nucleus B; nucleus B projects to Nucleus C. This issue may seem like a subtlety, but it is critical to understand what we mean when we say “project”.

“Project” also indicates the direction of information flow: from the cell body, through the axon to the synapse, and thus to the next neuron/nucleus. In our schematic, Nucleus A projects to Nucleus B, but Nucleus B does not project to Nucleus A.

Functional Systems and Lesions In general, a functional system is directly associated with a set of pathways. The “somatosensory system” can be considered the set of pathways that carry sensory information from the skin, muscles, joints and viscera to the cerebral cortex, where stimuli can be perceived. The red lines in the figure represent part of the somatosensory (touch) system that carries information from the face. The pathway consists of a three-neuron chain. The first neuron has a cell body located in the trigeminal ganglion.

Remember that this “one neuron” represents many (probably thousands) of neurons that all have the same connections. The axon of that neuron enters the brainstem, represented here in two cross-sections, colored purple. The second neuron in the pathway is in the principal nucleus of the trigeminal complex; its axon travels in a tract called the trigeminal lemniscus to a structure in the forebrain called the ventral posterior medial nucleus of the thalamus (the forebrain is represented by the beige-shaded cross-section). In the thalamus, the axon of the second neuron synapses on the third neuron in the pathway. The third neuron has 13

Orientation to the NS Schofield an axon that travels to the primary somatic sensory cortex, where touch is perceived.

Note that we followed the neurons – first, second, third – in the order in which they would conduct information (from periphery to cortex). Throughout the course, we will see numerous figures like this one; the details of this particular pathway are not essential now (they will be in a few weeks!); right now, the idea is to understand how a complex pathway, made up of thousands of neurons and their axons, can be represented in schematic form.

A lesion is anything that interferes with neuronal function. If a lesion destroys a brain area, the function(s) associated with that area and system is/are lost. If a lesion interrupts a pathway (by destroying a nucleus or fiber tract), the function is lost. The images below show two examples of lesions: a hemorrhage (resulting from a stroke) and a tumor, which compressed brain tissue to such an extent that it ceased to function.

A cerebral hemorrhage. Wellcome Images. file: cerebral hemorrhage.jpg

Example of a tumor. Wellcome Images. file: brain tumor.jpg

A note on anatomical images: The image of the tumor, above right, is easy to orient to because the whole brain is shown. What about the image of the hemorrhage, upper left? Which side of the brain has the lesion? Unfortunately, there are two different conventions: most clinical images are shown as if the patient is facing you, so the lesion above would be on the left side of the brain. However, many anatomical images are shown with “left on the left”; in such a case, the lesion above would be on the right side of the brain. How do you know the orientation? YOU HAVE TO LOOK AT THE LABELS; do not assume one convention or the other (the labels are not provided in this image, so you simply do not know).

Lesions generally lead to deficits with characteristics – specifically, the nature and the distribution of the deficits – that correlate precisely with the location of the lesion in the nervous system.

In Medical Neuroscience, we will use lesions to help us understand normal brain organization and function.

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Orientation to the NS Schofield

Three main pathways An important step in understanding the brain, and one of the long term goals of our course, is to develop a sense of its three-dimensional anatomy. As we describe the major brain regions during this first week, we will refer to three major pathways that underlie our sense of touch and our ability to control our muscles voluntarily. These pathways will be considered in greater detail later in the course, but for now we introduce a “lite” version of each so that we can relate brain regions to some of the important functions associated with these major pathways. Most of you are probably already familiar with the idea that a stroke in one brain hemisphere can lead to paralysis and loss of sensation on the opposite side of the body. As you will see, the pathways that underlie motor control and the sense of touch and pain cross the midline. Understanding where the pathways cross will be key to understanding the distribution of the deficits.

As you may recall from previous courses, most movement and sensation associated with the head is controlled via cranial nerves. For our use of the three pathways, we will skip the cranial nerves and focus on movement and sensation of the body (excluding the head).

Voluntary motor control: the corticospinal system The corticospinal system originates in the cerebral cortex and terminates in the spinal cord, where it activates neurons that directly innervate the muscles. Thus, this is a “2neuron” system: the first neuron is in the cortex and sends its axon all the way to the spinal cord, where it contacts (forms a synapse with) the second neuron. The second neuron, with its cell body in the spinal cord, has an axon that leaves the central nervous system to innervate a particular muscle.

Activation of this pathway leads to a contraction in the muscle. Voluntary movement ensues when the cortex sends a signal through this pathway. Damage to this pathway causes loss of the ability to contract the muscle; i.e., paralysis.

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Orientation to the NS Schofield

Two pathways for the sense of touch The sense of touch has multiple components (vibration, pressure, etc.); for now, we will distinguish between “fine touch” and pain. This pathway takes 3 neurons to get information from receptors in the periphery into the nervous system and “up” to cerebral cortex where the touch is perceived. Activity in the pathway is linked to the perception of touch or of pain.

If both pathways are damaged, there can be total loss of sensation (i.e., anesthesia). If just one pathway is damaged, there can be more limited loss of sensation (e.g., loss of pain sensation = analgesia).

Fine Touch (DC/ML) Fine touch is carried by three neurons from the periphery to the cerebral cortex. Along the way, the axons course in tracts known as the dorsal columns and the medial lemniscus, so this pathway is often referred to as the dorsal column/medial lemniscal pathway (hence, DC/ML).

Pain (ALS) The pathways that carry information about pain are rather complicated (more about that later) but for now we will focus on the pathway that carries pain information to the cerebral cortex. This allows both localization and perception of pain. As these axons course through the central nervous system, up through the spinal cord and brainstem, they occupy a generally “anterolateral” position. Thus, the overall term is the anterolateral system, or ALS.

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Orientation to the NS Schofield

Lesion of a pathway leads to loss of the function(s) associated with that pathway The figure shows schematics of the fine touch pathway with lesions indicated at different points (marked A and B) along the pathway in two different patients.

Assume that each patient is “facing us” so the right side of the body is to the left of the dashed line. Thus, Patient 1 has lesion A is on her right side whereas our Patient 2 has lesion B on his left side. Despite the difference in locations of the lesions, both patients have lost fine touch on their left side. Thus, Patient 1’s sensory loss is contralateral to her lesion, whereas Patient 2’s sensory loss is ipsilateral to his lesion.

Given what you know now, if we were to present these two patients to you, stating that each one had lost the sense of fine touch in his/her left hand, you could perhaps figure out that each is likely to have a lesion in their fine touch (DC/ML) pathway. Without more information you could not make predictions about lesions at A or B. As we go through the course, you will learn the key steps for making such a distinction.

Review questions and supplemental notes In this and my future lectures, I will put review questions at the end of the notes. For this lecture in particular, there are additional “supplemental” notes after the review questions that cover a few anatomical terms that we expect you know from previous course (e.g., Human Structure). We will use these terms extensively, and provide the supplemental notes to ensure that you can review the terms and, if any confusion arises, ask for clarification.

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Orientation to the NS Schofield Review questions 1. The nucleus labeled “A” projects to which of the nuclei? Which nucleus is a source of afferent projections to nucleus B? Which nucleus is a target of efferent projections of Nucleus B? Does Nucleus A project to Nucleus C?

Image by BSchofield; file: schem pathnolabel.jpg

2. If a person has a lesion of his spinal nerves as they exit the right side of his spinal column, which side will his sensory deficit be on?

3. True/False: The dorsal column pathway shows that neurons in the skin project to the somatosensory cortex.

4. The thoracic part of the spinal cord is (choose one): rostral OR caudal to the cervical spinal cord?

5. The midbrain is (choose one): rostral OR caudal to the medulla.

6. True/False: Anatomical and clinical images always show the structures as if the patient is facing you, with the patient’s left side on the right side of the image.

7. The cerebellum is _________ to the occipital lobe. a. anterior b. inferior c. posterior d. superior 8. The large bundle of fibers that connects the left and right cerebral hemispheres is called the a. cerebellar peduncle b. cerebral cortex c. cerebral peduncle d. corpus callosum 9. The island of cortex that is visible when you pry open the lateral fissure (lateral sulcus) is called the a. cerebellar cortex b. insula c. Sylvian cortex d. temporal lobe

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Orientation to the NS Schofield 10. The left side of cerebral cortex is concerned primarily with the (choose one) LEFT/RIGHT side of the body.

11. Pain sensation is carried primarily by which of the following pathways? a. anterolateral system b. corticospinal system c. dorsal column/medial lemniscus system 12. Corticospinal fibers project directly to skeletal muscles. TRUE/FALSE 13. A lesion in the dorsal column/medial lemniscal system can lead to a deficit ipsilateral or contralateral to the lesion. TRUE/FALSE

Supplemental Information

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Orientation to the NS Schofield

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Blood Supply, Meninges and CSF Mellott adopted from Schofield

BLOOD SUPPLY, MENINGES AND CEREBROSPINAL FLUID LEARNING OBJECTIVES Upon mastering this material, the student will be able to: 1. Describe the clinical significance of blood supply to the brain and spinal cord.

2. Describe the major branches and distribution of vertebrobasilar (posterior) and internal carotid (anterior) cerebral arterial systems.

3. Describe the functional organization of brainstem blood supply in terms of paramedian, short circumferential and long circumferential arteries.

4. Identify the components and clinical significance of the great arterial circle.

5. Describe the general organization of venous drainage of the CNS. 6. Describe the general function of three meningeal layers of the brain and their relationships to one another and to the central nervous system.

7. Explain the basics of brain herniation in the context of dural folds and the supratentorial and infratentorial compartments of the cranial cavity.

8. Describe the ventricular system and the source, flow, and elimination of cerebrospinal fluid (CSF).

KEY TERMS anterior (frontal) horn of lateral ventricle anterior cerebral artery anterior communicating artery aqueduct of Sylvius arachnoid granulation arachnoid mater atrium of lateral ventricle basilar artery body of lateral ventricle cavernous sinus central canal cerebellomedullary cistern cerebral aqueduct choroid plexus cisterna magna confluens of sinuses diaphragma sella dura mater falx cerebri foramen magnum fourth ventricle glymphatic system great arterial circle (of Willis)

herniation hydrocephalus inferior (temporal) horn of lateral ventricle inferior petrosal sinus inferior sagittal sinus infratentorial compartment internal carotid artery internal jugular vein interpeduncular cistern interventricular foramen (of Monro) lateral aperture of fourth ventricle (foramen of Luschka) lateral ventricle long circumferential arteries lumbar cistern median aperture of fourth ventricle (foramen of Magendie) middle cerebral artery paramedian arteries pia mater pontocerebellar cistern 1

posterior (occipital) horn of lateral ventricle posterior cerebral artery posterior communicating artery short circumferential arteries sigmoid sinus sphenoparietal sinus straight sinus subarachnoid space superior cistern superior petrosal sinus superior sagittal sinus supratentorial compartment tentorial notch (incisure) tentorium cerebelli third ventricle tonsillar herniation transverse sinus uncal herniation venous lacunae vertebral artery vertebrobasilar system

Blood Supply, Meninges and CSF

Reading The material you need to know is included in these notes. You can use the Appendix (“Survey of Human Neuroanatomy�) in your Purves text to review and provide another perspective. We will also cover this topic intensively in the lab, and the Haines atlas includes a great deal of relevant information. For example, Chapter 2, on the external morphology of the CNS, has many pictures of the vasculature.

Image Acknowledgments: used, with permission, from Purves, Neuroscience, 6th Edition, Sinauer Haines Neuroanatomy in Clinical Context, 9th Edition, Wolters Kluwer Netter Presenter Image Copyright 2003 Icon Learning Systems. All rights reserved.

BR Schofield, 2017-20.

Outline Overview Blood supply: Clinical significance Blood supply and the midline Blood supply to the brain: anterior and posterior circulations Vertebrobasilar system (the posterior circulation) General plan of arterial branches to the brainstem Internal carotid blood supply (the anterior circulation) Great arterial circle Venous drainage of the nervous system Meninges: normal structure Dura mater, dural folds and venous sinuses Arachnoid mater Subarachnoid cisterns Pia mater Spinal cord meninges Meninges: Clinical issues Venous sinuses Brain herniation The ventricular system Main components Cerebrospinal fluid (CSF) CSF production: choroid plexus CSF circulation and resorption Clinical issue: Lumbar puncture Hydrocephalus Glymphatic system Pain, the brain and meninges Review Questions

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Blood Supply, Meninges and CSF

INTRODUCTION Overview We will start with a description of blood supply to the nervous system, then move to meninges and venous drainage of the nervous system. Finally, we consider the cerebrospinal fluid (CSF) and the system of ventricles (spaces) within the brain where CSF is produced and circulates as well as the spaces outside the brain where CSF circulates and gets resorbed. Clinical significance relates to many facets of these topics and will be discussed at the appropriate time.

Blood Supply: Clinical significance Roughly half of all CNS clinical problems are vascular. This reflects the high oxygen consumption of the CNS; the brain makes up ~2% of body weight but accounts for ~20% of the body’s oxygen use. If the brain is deprived of oxygen for a short time (1012 seconds), loss of consciousness can occur; irreversible brain damage occurs after 3-5 minutes. Loss of blood supply to the spinal cord (e.g., from unintended compression of an artery during abdominal surgery) can cause paralysis.

In the lab you will identify the major vessels on the brain and spinal cord on gross specimens and in radiologic images (angiograms) and magnetic resonance (MR) images. In this lecture, we will focus on vessels (mainly arteries) that are visible on the surface of the brain and spinal cord. Branches of these vessels penetrate the underlying tissue to supply specific regions. Details that you need to know about the internal vessels will be covered in later lectures, first in Module 1 lectures on regional anatomy (e.g., spinal cord, medulla, etc.) and later as they relate to specific functional systems (e.g., somatosensory system for sense of touch) and finally in the context of patient case presentations.

Blood supply and the midline In general, a given artery supplies tissue on just one side of the nervous system (see figure). As a result, a vascular accident usually causes damage on just one side of the nervous system. There are exceptions, but the general rule can be quite helpful in understanding the pattern of deficits that result from a vascular accident.

Anterior view of left carotid artery. Haines atlas, fig 10-3.

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Blood Supply, Meninges and CSF

BLOOD SUPPLY TO THE BRAIN: ANTERIOR AND POSTERIOR CIRCULATIONS The blood supply to the brain originates from the internal carotid arteries and the vertebral arteries. The left and right vertebral arteries join to form the basilar artery and together are referred to as the vertebrobasilar system. The vertebrobasilar system forms the posterior circulation, which supplies the posterior cerebrum, brainstem, cerebellum and upper part of spinal cord. The internal carotid system forms the anterior circulation, which supplies much of the cerebrum. We will consider each system separately, then look at the great arterial circle, which connects the two systems.

Blood supply to the brain.

Vertebrobasilar system (the posterior circulation) The vertebral arteries originate from the subclavian arteries. Each vertebral artery travels superiorly through the transverse foramina of the cervical vertebrae. The arteries enter the skull through the foramen magnum to travel anterior to the medulla.

The two vertebral arteries join together at the pons-medulla junction to form a single basilar artery on the midline. The terminal branches of the basilar artery are the left and right posterior cerebral arteries. Together, the vertebrobasilar system supplies blood directly to the brainstem, cerebellum and parts of the cerebrum. It also gives rise to arteries that supply the rostral levels of the spinal cord. We will consider each of these areas in turn, but first we examine the general pattern for blood supply to the brainstem.

General plan of arterial branches to the brainstem. The main arteries are located on the ventral (anterior) surface of the brainstem. Each of the main arteries gives rise to

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Blood Supply, Meninges and CSF branches that encircle the brainstem. These branches can be categorized into 3 groups: 1. The shortest branches supply tissue along the midline. These arteries are called paramedian branches ( “1” in figure).

2. Short circumferential branches (“2” in figure) travel laterally along the ventral surface, then penetrate the brainstem to supply tissue lateral to that supplied by paramedian vessels.

3. Long circumferential branches (“3” in figure) wrap around the brainstem to supply the most lateral areas of the brainstem and in many cases provide additional blood supply to more dorsal (posterior) structures (e.g., the cerebellum).

The long circumferential arteries tend to get their own special names (they are generally descriptive of the termination of the vessel, e.g. “cerebellar” or “cerebral”). The shorter branches off the main arterial trunks are generally not specifically named (we simply refer to “the paramedian branches off the basilar artery”, for example).

General plan of arterial supply to brainstem. Image by BSchofield.

File: brainstem artery schem.png

“Main” artery trunk vs. brainstem division: posterior cerebral arteries midbrain basilar artery pons vertebral arteries medulla You should associate each main branch with its brainstem counterpart; realize that some of these arteries supply areas “Main” artery trunk vs. brainstem division: beyond the brainstem (the vertebral artery supplies upper spinal cord; the posterior cerebral arteries midbrain posterior cerebral artery, as its name basilar artery pons vertebral arteries medulla implies, supplies the posterior Basilar artery (pons and cerebellum) cerebrum).

Paramedian branches

You will learn the specific arteries and their distribution as we describe each of the major nervous system subdivisions (i.e., in the upcoming lectures on regional anatomy), and you will identify many of these vessels in the laboratory.

Short circumferential arteries (of basilar) (“short circum”) Long circumferential arteries: • Anterior inferior cerebellar artery (AICA) • superior cerebellar artery (sup. cerebellar a.)

Netter, fig. I.47 Medical Neuroscience

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*see other brainstem areas in lab Schofield

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Blood Supply, Meninges and CSF

Internal carotid artery (the anterior circulation) Each internal carotid artery passes through the carotid canal in the skull, penetrates the cavernous sinus and enters the cranial cavity just behind the orbit of the eye, adjacent to the optic nerve. At this point, it branches and forms several components of the great arterial circle. You will learn the distribution of these arteries in the upcoming lectures on regional anatomy, and you will identify these vessels in the laboratory.

Branches of the internal carotid and the great arterial circle

The great arterial circle.

Great arterial circle (circle of Willis) The great arterial circle is located on the inferior surface of the brain. It is formed by components of the anterior circulation (internal carotid system) and the posterior circulation (vertebrobasilar system), which are typically connected on each side by the posterior communicating arteries.

Main components of the great arterial circle: 1. internal carotid artery (2) 2. anterior cerebral artery (2) 3. anterior communicating artery (1) 4. posterior communicating artery (2) 5. posterior cerebral artery (2) Clinical Significance There are at least 2 major clinical issues associated with the great arterial circle.

First, collateral circulation: the presence of a circle means that a blockage in one area may be compensated for by flow through another branch. Interestingly, there are substantial normal variations between individuals; the posterior communicating artery is commonly quite small on one side (or even missing!). This may not present a

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Blood Supply, Meninges and CSF problem until some blockage shows up that might have been compensated by a larger artery.

The second clinical issue is that the great arterial circle gives rise to many small branches originating from large vessels (drawn but not labeled in the figure above).

These supply structures in the diencephalon and telencephalon. Small vessels originating from large vessels sets up a prime opportunity for a clot or a piece of plaque that has originated elsewhere to become lodged in one of these small arteries. Of course, a small artery supplies only a small volume of tissue, but some of these “small” areas contain fiber tracts that carry critical information to or from cerebral cortex. Thus, a “small” stroke can lead to major consequences. You will understand the nature and variety of these consequences as you learn how these vessels supply deeper structures in the diencephalon.

VENOUS DRAINAGE OF THE NERVOUS SYSTEM From a clinical perspective, the venous system of the CNS is less important than the arterial system. It has lower pressure than arteries, so strokes involving veins are comparatively rare. In addition, the veins are highly anastomotic and lack valves, so there is rarely a blockage of blood flow that compromises brain tissue. The figure to the right gives an overview of venous drainage for the brain. Shown are venous sinuses through which most of the cerebral blood supply drains into the internal jugular vein. The venous sinuses are formed by the dura mater, which we will cover in more detail below. We will consider the veins that feed into the venous sinuses in more detail in the laboratory, where you will identify a few major veins and the venous sinuses in multiple settings (e.g., radiologic images, skull models, special dissections of meninges and brains) and review their location on the brain specimens.

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Final drainage of venous blood from the brain occurs through venous sinuses into the internal jugular vein.

Blood Supply, Meninges and CSF

MENINGES: NORMAL STRUCTURE The meninges encase the brain and spinal cord and their outer layer is continuous with the epineurium of spinal and cranial nerves.

The meninges comprise three layers; from outer to inner, these are the dura mater, arachnoid mater and pia mater. In most common usage, the “mater” is left off and the layers are referred to simply as dura, arachnoid and pia. Together, these layers support the brain and spinal cord.

Dura mater, dural folds and venous sinuses The dura in the skull comprises 2 layers (see Figure, image at bottom). The outer periosteal layer adheres closely to the skull.

The inner meningeal layer closely adheres to the periosteal layer in most areas. In several locations, the meningeal layer separates from the periosteal layer and forms a fold of dura that extends into the cranial cavity and usually is located between two parts of the brain. The Meningeal layers on brain. largest folds are known as the falx cerebri and the tentorium cerebelli. “Falx” means “sickle”; the falx cerebri is a sickle-shaped fold of dura between the two cerebral hemispheres. The second major fold of dura is the tentorium cerebelli, a pyramid-like fold of dura that forms a tent over the cerebellum. The tentorium cerebelli thus separates the cerebellum from the occipital lobes of the cerebral cortex. It also divides the cranial vault into two distinct regions: a supratentorial compartment and an infratentorial compartment. There is an opening in the tentorium cerebelli called the tentorial notch, or tentorial incisure.

This opening contains the brainstem (in particular, the midbrain). We will consider the compartments and the tentorial notch in more detail below, in the context of brain herniation. First, we finish consideration of the dural folds. A small “falx cerebelli” is located along the midline, below the tentorium cerebelli, associated with the cerebellar hemispheres. Where these folds attach to the skull, they leave a small open channel that functions as a vein (see figure). These venous sinuses are the main route for blood to exit the cranial cavity. The falx cerebri forms the superior sagittal

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Blood Supply, Meninges and CSF

Left: falx cerebri (red) and tentorium cerebelli (green).

Right: coronal section through head to show meningeal layers and two venous sinuses, superior sagittal sinus and inferior sagittal sinus, formed by the falx cerebri. From Netter, Fig. I.41.

sinus where it attaches to the skull.

Another venous sinus, the inferior sagittal sinus, is formed along the inferior “free” (unattached) edge of the falx cerebri. The tentorium cerebelli forms the transverse sinuses (one on each side, along the occipital bone), and a straight sinus where the tentorium cerebelli joins the falx cerebri. The two transverse sinuses, the straight sinus, and the superior sagittal sinus meet at the confluens of sinuses. You can see all these sinuses in lab (check out the special dissection that shows the dural folds and the tentorial notch with the midbrain inside).

Tentorial compartments. Haines Atlas, fig. 9-1.

There are some additional sinuses along the skull surface (in the lab, you can see these along the inner surface of the skull; the image below depicts their alignment on the brain surface). The sphenoparietal sinus occurs along the inner surface of the parietal bone and then traverses the surface of the sphenoid bone before emptying into the cavernous sinus. The superior petrosal sinus and the inferior petrosal sinus run along the superior or inferior margin of the petrous part of the temporal bone (hence the “petrosal” name). The transverse sinus drains into the sigmoid sinus, which drains directly into the internal jugular vein.

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Blood Supply, Meninges and CSF

There are two other dural sheets that you should recall. The first forms the lateral wall of the cavernous sinus; the medial wall of the cavernous sinus would be formed by the periosteal layer of dura. Finally, we mention a dural sheet that does not form a sinus but has clinical relevance: the diaphragma sella, or sellar diaphragm, the dural sheet that overlies the pituitary gland.

This sheet covers the sella turcica (Turkish saddle), on which the pituitary gland sits. A small opening in the diaphragma sella allows the pituitary stalk to connect with the hypothalamus.

This opening is smaller than the Venous sinuses on inferior surface of brain. Haines pituitary gland itself, which explains Atlas, 2-19. why the pituitary is not still attached to the hypothalamus in any of the brains in the lab (it tore off and was left in the skull when the brain was removed).

Another place where the cranial dural layers separate is on the superior surface of the brain, just lateral to the midline. Here, the two dural layers separate to form numerous venous lacunae (singular: lacuna). These lacunae are the sites where the arachnoid granulations pierce the dura (see figure above showing the arachnoid granulations; more about these structures later in this lecture). The lacunae contain venous blood and are continuous with the superior sagittal sinus.

Arachnoid mater The outer surface of the arachnoid adheres to the inner surface of the dura. The arachnoid is so called because of the many thin “spider web-like” fibers that extend from the outer part of the arachnoid through a fluid-filled space to the next inner layer, the pia. The fluid is cerebrospinal fluid, or CSF, which fills the subarachnoid space.

The major arteries supplying the CNS travel in the subarachnoid space; to reach the brain or spinal cord, they must penetrate the subjacent pia. You will see the arachnoid on some of the specimens in lab, although it will have collapsed onto the underlying brain tissue because the CSF Meningeal layers on brain. has leaked out as soon as the arachnoid was pierced (as needed for removing the brain from the skull). The arachnoid will look like a translucent film wrapping over the brain; it stretches “over” the sulci of the cerebral cortex. In some areas the arachnoid forms a 10

Blood Supply, Meninges and CSF relatively thin (a few millimeters) space filled with CSF as the arachnoid layer wraps the brain. At other areas, the layer is farther removed from the brain, leaving a larger subarachnoid space. These enlargements of the subarachnoid space are called cisterns. A final arachnoid structure is known as an arachnoid granulation. These granulations serve a specific function associated with the CSF, which we will discuss below.

Subarachnoid cisterns The subarachnoid space has several enlargements called cisterns. Cisterns are usually named according to the brain structures with which they have borders.

•

•

• • •

•

pontocerebellar (or) cerebellopontine cistern around lateral surface of pons cerebellomedullary cistern adjacent to cerebellum and medulla; also called cisterna magna because of its large size. interpeduncular cistern between the 2 cerebral peduncles chiasmatic cistern next to the optic chiasm quadrigeminal cistern adjacent to the quadrigeminal bodies (the superior and inferior colliculi).

This cistern is also frequently called the superior cistern lumbar cistern at lumbar level of spinal column.

CSF flow. from Netter, Fig. I.44.

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Blood Supply, Meninges and CSF

Pia mater The pia mater is a very thin layer (1 or a few cells thick) closely following the surface of the brain and spinal cord. So, unlike dura and arachnoid, pia mater actually dives into the sulci (the grooves) that characterize the surface of the cerebrum and cerebellum. The figure shows the meningeal layers in a section through the top of the brain.

Spinal cord meninges The meninges around the spinal cord are continuous Meningeal layers on brain. Purves, A21. with and quite similar to those around the brain in most respects.

However, a few differences are important. As for the brain, pia is closely adhered to the surface of the spinal cord, but in several places it extends beyond the cord to help anchor it in the vertebral column.

Along each lateral Filum terminale (labeled Denticulate ligaments. From Haines, surface of the cord, filum terminale internum).

Fig. 2-2.

Haines Atlas, fig. 2-4. there are about 21 flat, arrowhead-like extensions where the pia stretches across the subarachnoid space to attach at points to the dura. These are called denticulate ligaments, referring to their resemblance to shark teeth. Also, at the caudal end of the cord, the pia continues as a fibrous cord, the filum terminale. The filum terminale extends caudally to reach the end of the dural sac, then gets wrapped in dura to form the coccygeal ligament (described below).

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Blood Supply, Meninges and CSF Another difference between skull and spinal column: In the spinal column, there is space between the outer surface of the dura and the vertebral bones (there is no epidural space in the skull). This epidural space in the spinal column contains fat as well as the spinal nerves as they travel between spinal cord and the periphery. These nerves, and in particular the sensory fibers that continue into the dorsal roots, are the targets of anesthetic drugs for epidural anesthesia.

Meninges around spinal cord; blue shading is subarachnoid space, with arteries present. Meningeal layer of dura encapsulates this space. Note natural epidural space (white area) between meninges and vertebral body. Haines Atlas Fig. 9-9.

The spinal cord ends at about vertebral level L2, but the dura and arachnoid continue caudally to about vertebral level S2. At this point, the dura collapses to form the coccygeal ligament (with the filum terminale inside), which extends to anchor the dural sac at the coccyx.

MENINGES: CLINICAL ISSUES The meninges are associated in numerous ways with clinical issues. We first discuss some issues related to venous sinuses and herniation syndromes (related to the dural folds), lumbar puncture and finally consider pain and the meninges.

Epidural space, spinal column, midsagittal MRI. Haines Fig. 2-4.

Venous sinuses The main clinical problem we will discuss is associated with the cavernous sinus.

Venous blood has multiple routes for exit from the skull, so these problems are less related to blood flow per se but are associated with other components of the cavernous sinus. An infection or tumor in the area could compromise the internal carotid artery, and thus cause a major problem related to the anterior cerebral circulation. A stroke in this area could be fatal immediately; a more limited stroke (perhaps partially

13

Blood Supply, Meninges and CSF compensated for by collateral circulation from the great arterial circle) could still lead to both motor and sensory problems. Also located in the cavernous sinus are cranial nerves, including oculomotor, trochlear and abducens nerves as well as ophthalmic and maxillary branches of trigeminal nerve.

Problems with these nerves, especially those controlling eye movements and pupil diameter, are easily assessed.

Brain herniation

Venous sinuses. Haines Atlas Fig. 2-19.

“Herniation� in this context refers to part of the brain getting pushed out of place, leading to neural deficits. These are clinically very important but can also be hard to understand. First, think about the brain in the cranial cavity. If you were simply to push downward on the brain, you might imagine the inferior part of the cerebellum getting pushed into the foramen magnum. In fact, this occurs, and can be fatal. Why? Well, it certainly isn’t good for the cerebellum to get pushed around, but in this case (as for many of the herniation syndromes), the bigger problems are associated with other structures that get compromised. In this case, the cerebellum starts to crush the lower medulla and/or the vertebral arteries, which normally traverse the foramen magnum. As you might imagine, constricting the vertebral arteries can compromise the function of the brainstem regions that these arteries supply. The brainstem is essential for life support (e.g., it contains essential regions for cardiac and respiratory control), so death can result from such a herniation.

Even if the arteries maintain sufficient flow, the medulla and its life support areas can get directly compressed as the cerebellum pushes into the foramen magnum. So, this type of herniation can be quite dangerous. Herniations are often named according to the part of the brain that shifts out of place. The part of the cerebellum at issue here is called the tonsil, so we have a tonsillar herniation. The herniation occurs when something (like blood collecting from a broken vessel or from a tumor growing) increases pressure in the cranial cavity.

A key step in understanding brain herniation is to understand the concept of supratentorial and infratentorial compartments. Recall that these 2 compartments of the cranial cavity are separated by the tentorium cerebelli.

The supratentorial compartment is divided into left and right sides by the falx cerebri (see figure). As you will see in lab, the tentorium and falx are quite stiff; they are virtually immovable. The tonsillar herniation described above would most likely result from increased pressure in the 14

Blood Supply, Meninges and CSF infratentorial compartment. Alternatively, increased pressure in the infratentorial compartment could push brain tissue upward, into the tentorial notch.

Increased pressure in a supratentorial compartment can also cause herniations. A common one pushes the medial part of the temporal lobe over the edge of the tentorium cerebelli into the tentorial notch. Once again, the herniation is named according to the bit of brain tissue that moves out of place; in this case, the relevant part of the temporal lobe is called the uncus, giving the name uncal herniation. And again, the deficits are associated not with the herniating tissue per se, but with structures that get compressed (in this case, the oculomotor nerve and the cerebral peduncle are common “victims�).

In lecture, I will present the 2 slides below showing examples of two common types of herniation. The images may be challenging for you to interpret at this point (though not so challenging by the end of our course!). Do not worry if these do not make sense to you yet (these images are beyond what you need to understand for exam 1); spend time in lab and you will get to understand these clinically important issues.

Lecture slide

Lecture slide

Now, back to our regularly-scheduled lecture notes.

15

Blood Supply, Meninges and CSF

THE VENTRICULAR SYSTEM The figure shows the ventricular system as it appears in a section through the neural tube during an early (left image) and later (middle) stage of development. The adult appearance of the ventricular system is shown from an anterolateral view (right image).

Development of the ventricular system. From Netter, Fig. I.77.

The main components of the ventricular system are: • lateral ventricles (2 of them, one in each cerebral hemisphere) • interventricular foramen (foramen of Monro) • third ventricle • cerebral aqueduct • fourth ventricle • lateral aperture of fourth ventricle (foramen of Luschka), 2 of them, one left and one right • median aperture of fourth ventricle (foramen of Magendie) The structures are listed above in the order in which CSF moves through them. The three apertures of the fourth ventricle (2 lateral apertures and 1 median aperture) allow the CSF to drain out of the CNS and into the subarachnoid space that surrounds the CNS. You will use models, special dissections and examination of the brain slabs in the lab to learn the important structural aspects of these cavities.

16

Blood Supply, Meninges and CSF

The lateral ventricle has several parts: • anterior horn (= frontal horn) • body • atrium • posterior horn (= occipital horn) • inferior horn (= temporal horn)

Cerebrospinal fluid (CSF) The cerebrospinal fluid (CSF) is a clear, colorless liquid produced from blood plasma. It surrounds the brain and spinal cord and serves several functions.

The ventricular system (shown in blue). A. view from the left

Functions of the CSF side of the brain; B view from above.

• buoyancy for the brain (the brain nearly floats in CSF) • cushioning (protection against physical trauma) • removing metabolites from the CNS • helping to maintain proper ionic environment for CNS

The average adult brain weighs about 1400 g. When “floating” in CSF, the brain’s weight is about 25 g (about equal to 5 nickels!); this buoyancy helps to prevent the weight of the brain from damaging itself or compressing blood vessels that are “underneath” (i.e., inferior, when a person is standing). CSF is produced by choroid plexus, a specialized tissue located within numerous cavities in the brain. These cavities, called ventricles, are the derivatives of the cavity in the neural tube from which the brain and spinal cord develop. CSF flows through the ventricles and their connecting channels and then exits the brain to fill the subarachnoid space around the brain and spinal cord.

CSF production: choroid plexus The total volume of CSF is generally 150-270 ml in adults, with about 20% of the volume in the ventricular system and the remainder in the subarachnoid space. Overall, CSF is produced at about 500-700 ml/day, so the total volume is replaced every ~3-4 17

Blood Supply, Meninges and CSF times per day. With this rate of change, there is sufficient “turnover� that sampling the CSF, as done in a lumbar puncture (or spinal tap), can be a useful assessment of the CSF overall.

CSF is produced by modified ependymal cells that form a distinctive tissue known as choroid plexus located in several places within the ventricular system (see Figure). In each lateral ventricle, the choroid plexus is located along the medial wall. It extends from the inferior horn superiorly into the atrium, then anteriorly into the body of the lateral ventricle, extending as far anteriorly as the interventricular foramen. [So, if that is the full extent of the choroid plexus in the lateral ventricle, which parts of the lateral ventricle lack any choroid plexus? Answer at end of this set of notes]. The strip of choroid plexus extends into/through the interventricular foramen into the third ventricle, where it forms a strip of choroid plexus found along the roof of the third ventricle. The final piece of choroid plexus is located in the fourth ventricle and is not attached to the choroid plexus in the third ventricle. The choroid plexus of the fourth ventricle commonly extends laterally through the lateral apertures such that you can usually see a bit of choroid plexus on the lateral surface of the brainstem. You will see this in lab; the choroid plexus has a distinctive appearance and seeing it on the lateral brainstem will provide a visual guide to the location of the lateral apertures of the fourth ventricle.

CSF circulation and resorption CSF flows from the lateral ventricles through the interventricular foramina (foramina of Monro) into the third ventricle. Then, it flows through the cerebral aqueduct into the fourth ventricle. The CSF leaves the fourth ventricle through the median aperture and lateral apertures (a.k.a., foramina of Luschka and Magendie). The median aperture drains into the cerebellomedullary cistern (cisterna magna). The lateral apertures empty into the pontocerebellar (or cerebellopontine) cistern. Recall that the central canal is usually not patent, so all CSF in the fourth ventricle typically leaves via the 3 apertures into the subarachnoid space. Then 18

Blood Supply, Meninges and CSF the CSF travels within the subarachnoid space and flows into the venous system through the arachnoid granulations (arachnoid villi). These granulations are located on the superior surface of each cerebral hemisphere, just lateral to the midline.

There are no valves and no contractile forces devoted to moving the CSF, so what propels it and what direction does it flow within the subarachnoid space?

Propulsion is determined largely by the pressure exerted by the production of CSF. The only outlet from the ventricles is through the Arachnoid granulation (pink) penetrating the dura into a venous fourth ventricle foramina, so lacuna. from Netter, Fig. I.41. all flow proceeds from lateral ventricles toward the fourth ventricle. Flow in the subarachnoid space is determined mainly by where CSF enters the space and where it leaves; in other words, flow “starts” around the medulla and pons as CSF leaves the fourth ventricle. CSF eventually leaves the subarachnoid space via the arachnoid villi near the superior sagittal sinus, i.e., near the top of the brain. The fluid simply has to move from “source” around medulla to “outlet” superiorly. Gravity, and therefore body position, can play a role, as can body movement.

Clinical issue: Lumbar puncture The lumbar cistern is the simplest and safest place to obtain CSF for analysis, as might be done to look for red blood cells as a sign of subarachnoid hemorrhage. The key features in choosing this area are first that as a cistern, it contains CSF and, second, it lies inferior to the spinal cord itself, minimizing the possibility of accidentally damaging the spinal cord during the procedure. Of course, there are plenty of spinal nerves present in the lumbar cistern; these tend to move out of the way and avoid any serious damage during a spinal tap.

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Blood Supply, Meninges and CSF

Clinical issue: hydrocephalus Hydrocephalus, “water on the brain”, results when more CSF is produced than is reabsorbed.

Symptoms such as headache and nausea relate to increased intracranial pressure. Additional symptoms relate to specific brain regions compromised (which of course depends on the specific cause in the individual). Hydrocephalus can result from overproduction of CSF, impaired resorption of CSF, or a blockage of the flow of CSF (so-called “obstructive hydrocephalus”). A typical location for blockage of CSF is in the cerebral aqueduct (aqueduct of Sylvius), because of its small diameter. Blockage here leads to expansion of the lateral ventricles. In general, the buildup of pressure interferes with neuronal function directly and by compressing blood vessels, limiting blood supply. If hydrocephalus occurs in an infant prior to fusion of the skull bones and is untreated, the skull can grow to enormous size. The ventricles are exceptionally large and the brain generally fails to develop normally, leading to deficits and often early death. Another potential cause is a tumor that blocks CSF flow. The upper figure shows a tumor (the large white mass on the midline) originating from the choroid plexus of the third ventricle. The tumor itself has expanded the third ventricle but note also the dramatically enlarged lateral ventricles resulting from restriction of CSF flow through both interventricular foramina.

Tumor (white mass) of the choroid plexus in the third ventricle. Note enlarged ventricles (compare to image below, which shows blood in a posterior horn but in which the ventricles are relatively normal size).

Both images from Haines Atlas, Fig. 4-15D. See the parent figure in your Atlas for more detailed discussion and further examples.

A common treatment for hydrocephalus is placement of a shunt, or catheter, with one end in see legend above. a ventricle and the other end in another body region (often in abdominal cavity) where CSF can drain and be absorbed. A valve in the catheter limits flow to the proper direction and also limits the rate so as not to overdrain the ventricles.

The glymphatic system In the rest of the body (i.e., outside the nervous system), the lymphatic system parallels the vascular system to support immune function and provide transport for interstitial fluid back to the venous system. A “lymphatic” system has long been assumed to be absent from the brain. However, lymphatic vessels associated with the nervous system have recently been identified. They run along blood vessels, although their exact 20

Blood Supply, Meninges and CSF relationship to the meninges is still debated.

It is now believed that they function along with astrocytes to facilitate transport of water, macromolecules and some cells (i.e., rather typical “lymph”) from the interstitial space of the nervous system into the venous sinuses. The term “glymphatic” was coined to reflect the combined function of glial cells and lymphatic vessels. Some believe that this route is an important avenue by which CSF can exchange with the interstitial fluid and then get reabsorbed into the venous system (in parallel to the “classical pathway” of arachnoid granulation filtering CSF into the venous sinuses). The flow in this system is regulated to a great degree by aquaporin4, a water channel especially prominent in astrocytes. How is this relevant clinically? A current hypothesis is that dysfunction of this system would lead to reduced clearance of metabolic wastes, such as beta-amyloid or synucleins. Buildup of these molecules is closely associated with Alzheimer’s disease Glymphatic system. The lymphatic and Parkinson’s Disease, respectively. vessels are not drawn explicitly but are Interestingly, the glymphatic flow reportedly thought to lie along the veins and/or increases during sleep, supporting the idea arteries. that sleep provides an opportunity for the nervous system to “clean itself”. Flow through this system is largely passive, resulting from CSF pressure and from the pulsatile actions of arteries and arterioles.

21

Blood Supply, Meninges and CSF

REVIEW QUESTIONS The material in this lecture is very closely tied to that in the laboratory. If you find some of the questions challenging after the lecture, revisit them after you have completed the relevant laboratory exercises. These questions are repeated in the ppt with the answers highlighted.

1. Structures located next to the midline in the pons are most likely supplied by which type of artery? a. long circumferential artery b. paramedian artery c. short circumferential artery 2. Which artery provides the main supply to the medulla? a. basilar artery b. posterior cerebral artery c. vertebral artery 3. Which artery provides the main supply to the pons? a. basilar artery b. posterior cerebral artery c. vertebral artery 4. Which artery provides the main supply to the midbrain? a. basilar artery b. posterior cerebral artery c. vertebral artery 5. Which vein drains almost all cerebral blood out of the cranial cavity?

6. Which of the following structures lies between the left thalamus and right thalamus? a. foramen of Luschka b. fourth ventricle c. lateral ventricle d. third ventricle 7. Herniations are typically named according to the a. cistern they are closest to b. part of the brain compressed by the herniation c. part of the brain that gets displaced d. physician who first described the associated syndrome 8. Which ventricular structure(s) is/are associated with the (provide answer for each): a. hypothalamus b. medulla 22

Blood Supply, Meninges and CSF c. d. e. f.

midbrain pons spinal cord thalamus

9. Which of the following ventricular structures typically contain choroid plexus (choose all correct answers): a. anterior (frontal) horn of lateral ventricle b. atrium of lateral ventricle c. body of lateral ventricle d. central canal e. cerebral aqueduct f. fourth ventricle g. inferior (temporal) horn of lateral ventricle h. interventricular foramen i. lateral aperture j. median aperture k. posterior (occipital) horn of lateral ventricle l. third ventricle 10. Which type of glial cell is believed to facilitate glymphatic flow through brain tissue? a. astrocyte b. microglia c. oligodendrocyte 11. Which of the following ventricular structures are directly visible on a perfect midsagittal section of a human brain? a. atrium of lateral ventricle b. body of lateral ventricle c. central canal d. cerebral aqueduct e. fourth ventricle f. inferior horn of lateral ventricle g. interventricular foramen h. lateral aperture i. median aperture j. posterior horn of lateral ventricle k. third ventricle 12. Which cistern contains the nerves of the cauda equina?

13. An uncal herniation is associated with an increase of pressure in the a. infratentorial compartment. b. supratentorial compartment.

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1

Spinal Cord Learning objectives At the end of this lecture, students will be able to: • • • • •

Describe the spinal cord levels, relationship to the vertebral column and sensory/motor zones Explain the internal arrangement of the spinal cord, including subdivisions of white and gray matter Distinguish between gray and white matter as related to structure and function Identify general differences in spinal cord regions Know the blood supply of the spinal cord

Key Terms anterior horn anterior median fissure anterolateral system cauda equina central canal commissures corticospinal tract dermatomes dorsal column dorsal intermediate sulcus dorsal nucleus of Clark dorsal root ganglion dural sac enlargements fasciculus fasciculus cuneatus

fasciculus gracilis filum terminalis foramen magnum funiculus intermediate zone intermediolateral cell column laminae median fissure median sulcus medullary arteries myotomes parasympathetic nucleus pathway phrenic nerve posterior horn

Recommended Reading: Neuroanatomy 9th edition, Haines,D., Chapter2(pgs..8- 11), Chapter 6-1 to 6-9; Purves Neuroscience Appendix A2 – A7).

Illustrations: Human Anatomy, 7th Ed., Martini, F., et al. Pearson Neuroanatomy 9th edition, Haines, D. Lippincott

Spinal Cord: Basic Concepts 1. Extension/continuation of the brain 2. Surrounded by bone, the vertebrae 3. Contains two enlargements: Cervical (C4 to T1) and Lumbosacral (T11 to S1) Figure at right: Figure 14-1 Human Anatomy, Pearson 4. Segments and Exits

posterior median sulcus radicular arteries roots (dorsal and ventral) spinal accessory nucleus spinal anesthesia spinal arteries spinal nerves spinal tap spinocerebellar tract

2 The cord is divided into 31 segments. Each segment is identified by a letter and number designation.

Cervical Thoracic Lumbar Sacral Coccyx

Spinal Nerves: 31 8 12 5 5 1

Vertebrae: 33 7 12 5 5 4 (fused)

5. Spinal cord terminates at conus medullaris filum terminalis: pia mater that anchors the spinal cord to the coccyx cauda equina: “horse tail” spinal nerves from the lumbar and sacral segments dural sac: extension of dura to S2 6. Dermatomes Sensory innervation regions that can be traced to a spinal nerve/spinal level. Some examples: Hand (C5 to C8) Umbilicus (T10) Feet (L5 to S1) Sacrum (S2 to S4) Myotomes: Motor innervation regions Examples: Elbow flexion C5,6 Elbow extension C7 Knee flexion L5, S1 Knee extension L3, 4 Illustration (L) source: "Medical gallery of Mikael Häggström 2014".

Wikiversity Journal of Medicine 1 (2). DOI:10.15347/wjm/2014.008

7. Sensory nerves Afferents: Periphery → Spinal cord Receptor Dorsal and ventral rami (branches of spinal nerve) Spinal nerve (mixed sensory and motor) Dorsal root ganglion Dorsal root Dorsal (posterior) horn

3 8. Motor nerves Efferents: Spinal cord → Periphery Ventral horn Ventral root Spinal nerve (mixed motor and sensory) Dorsal and ventral rami (branches of spinal nerve) Effectors 9. Gray matter Synaptic interactions of sensory processing Synaptic interactions of movement and autonomics Sensorimotor integration (reflexes) 10. White matter Long ascending tracts Long descending tracts Axons terminating in other levels

Spinal Cord: Internal Arrangements 1. Overview A. Gray matter B. White matter C. Ventral (anterior) and Dorsal (posterior) horns D. Anterior median fissure Divides anterior part of spinal cord into halves Contains pia mater Branches of the anterior spinal artery E. Posterior median sulcus Divides posterior of spinal cord into halves Contains pia mater known as the posterior median septum F. Central canal Cerebrospinal filled space running the length of the spinal cord G. Commissures Gray (Lamina X) Anterior white commissure (just anterior to Lamina X)

2. Gray Matter Detail: Neurons and glia A. Four major regions, subdivided into ten laminae [Rexed’s Laminae] Posterior (dorsal) horn: Laminae I to VI Intermediate Zone: Lamina VII Anterior (ventral) horn: Laminae VIII and IX Central canal area (Gray commissure): Lamina X

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B. Posterior (dorsal) horn: Laminae I to VI I – Posterior marginal nucleus = pain and temperature (contributes to lateral spinothalamic tract) II – Substantia gelatinosa = pain and temperature (intersegmental column cells that synapse on cells in Lamina IV to VII) III and IV – Nucleus propius = touch and pressure (mechanoreceptors) V and VI – Base of posterior horn V – Neurons and dendrites of Lamina II VI – Small neurons participating in spinal reflexes C. Intermediate Zone: Lamina VII Dorsal nucleus of Clark (C8 to L3): The axons from these cells pass uncrossed to form the dorsal spinocerebellar tract, subserving unconscious proprioception from muscle spindles and Golgi tendon organs to the cerebellum Intermediolateral cell column (T1 to L2): Receives viscerosensory information and contains visceral motor neurons whose axons are preganglionic sympathetic fibers.

D. Anterior (ventral) horn: Laminae VIII and IX VIII – Modulates motor activity IX – Motor neurons (lower motor neurons) Arranged medial to lateral within Lamina IX Alpha (α)– Innervate extrafusal fibers for voluntary muscle contraction and maintenance of muscle tone Beta (β) – Innervate intrafusal muscle fibers, with collaterals to extrafusal fibers Gamma (γ)– Intrafusal fibers of muscle spindles; sensory proprioception E. Central canal area: Lamina X Commissural area (Gray) also contains decussating axons 3. White Matter Detail: Axons A. Surrounds gray matter B. Contains myelinated and unmyelinated nerve fibers (axons) C. Axons ascend and descend in the spinal cord D. Three large regions Posterior (dorsal) Lateral Anterior (ventral) E. Nomenclature Funiculus: morphological term for large group of nerve fibers Fasciculus: Smaller bundles of axons within a funiculus

Diagram showing the functional localization of motor neuron groups in the ventral gray horn of a lower cervical segment of the spinal cord.

Tract: Group of axons with same origin, destination, course and function. Specific tract name is usually derived from origin and termination (eg., corticospinal tract) Pathway: Entire neural circuit responsible for a function 4. Ascending Tracts (left portion of figure below) A. The Dorsal Columns • Comprise the posterior (dorsal) funiculus • Mediates conscious perception of most mechanical stimuli from the ipsilateral side • Proprioception, tactile and vibration information • Fasciculus gracilis (medial portion) conveys information from the lower limbs below T6 • Fasciculus cuneatus (lateral portion) conveys information from the upper limbs above T6

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B. Spinocerebellar Tracts • Anterior (ventral) and posterior (dorsal) spinocerebellar tracts convey information about muscles and joints • Part of the lateral funiculus C. Anterolateral system • Contains the spino-thalamic, spino-reticular, spino-mesencephalic and spino-hypothalamic tracts • Part of the lateral and ventral funiculus • Lateral spinothalamic conveys pain and temperature • Ventral spinothalamic conveys crude touch 5. Descending Tracts (right side of figure below) A. Lateral funiculus 1. Movement and motor control 2. Components Lateral corticospinal tract: source of conscious control of movement Lateral Reticulospinal tract: Automatic movements of location and posture; originates in medulla B. Anterior (ventral) funiculus 1. Associated with motor regulation 2. Components Reticulospinal: Automatic movements of locomotion and posture; originates in pons Vestibulospinal: Support posture and maintain balance Anterior corticospinal: Voluntary motion Medial longitudinal fasciculus: Motor to neck and axial muscles

Ascending

Descending

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Distribution of Gray Matter, White Matter and Nuclei in the Spinal Cord DIS

1. The size and shape of GM and WM varies with the vertebral level in the spinal cord

FC

2. Cervical regions (in general) contain more white matter due to the larger number of axons ascending and descending through this region.

3. Cervical (C4 to T1) and lumbar enlargements (T11 to S1) contain expanded gray matter due to large groups of motor neurons innervating upper (lateral ventral horn) and lower limbs (medial ventral horn).

ACC FC

4. Notable landmarks DIS Dorsal intermediate sulcus Separates fasciculus cuneatus (FC) from fasciculus gracilis P

ACC Spinal accessory nucleus: C1 to C5 Motor component for trapezius and sternocleidomastoid muscles P Phrenic nerve nucleus: C3 to C5 Motor component for diaphragm

DN IML

DN Dorsal nucleus of Clark: C8/T1 to L2/3 Sensory component for proprioceptors of hindlimb/cerebellum IML Intermediolateral column: T1 to L2 Sympathetic pre-ganglionic neurons SPN Sacral parasympathetic nucleus: S2 to S4 Parasympathetic pre-ganglionic neurons for pelvic viscera

SPN

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Blood Supply for the Spinal Cord Anterior Spinal Artery (one) Formed by union of vertebral artery branches Runs inferiorly in the anterior median fissure Central (sulcal) branches enter the spinal cord through the fissure Supplies approximately 2/3 of the spinal cord

Posterior Spinal Artery (two) Branch of either the vertebral artery or posterior inferior cerebellar artery Supplies approximately 1/3 of the spinal cord, primarily the dorsal funiculus Segmental Arteries (several; derived from numerous sources) A. Medullary arteries • Primarily associated with the cervical and lumbar enlargements • Great Anterior Segmental Medullary Artery (of Adamkiewicz) o An especially large medullary artery, usually on left side (65% of people) • Reinforces circulation to 2/3 of spinal cord • Bridge between segmental and spinal arteries B. Radicular arteries • Supply the anterior and posterior roots and DRGs (dorsal root ganglia) • Most are small

Area fed

by PSA

Area fed by ASA

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Venous drainage: Deoxygenated blood from the spinal cord drains into the anterior and posterior internal venous plexus, which is localized to the epidural fat between the dura mater and the inner bony surface of the vertebral canal. This blood is carried away from these plexuses via intervertebral veins, which connect with larger-diameter segmental veins (lumbar veins, posterior intercostal veins, etc.). Ultimately the deoxygenated blood is transferred into the azygous/hemiazygous/accessory hemiazygous sytem. Finally the blood drains into the right atrium of heart either via the SVC (azygous) or via brachiocephalic veins→SVC.

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Review Questions 1. The inability to breathe would suggest an injury to which region of the spinal cord?

A. Cervical B. Thoracic C. Lumbar D. Sacral E. Coccygeal 2. The fasciculus cuneatus would LEAST likely be present in which spinal cord region?

A. C1 B. T1 C. L1 D. S1 3. Insertion of a spinal needle for removal of a sample of cerebrospinal fluid should be performed at: A. An area just above the dural sac B. An area just below the dural sac C. The L1/L2 region D. The L3/L4 region E. At the conus medullaris 4. Occlusion of the posterior spinal artery would produce the greatest deficits in the: A. fasciculus proprius B. fasciculus gracilis C. Laminae VIII and IX D. rubrospinal tract E. dorsal nucleus of Clark 5. At the medulla-spinal cord junction, most fibers cross to form the lateral corticospinal tract. Consequently, lesions of the lateral corticospinal fibers on one side of the cervical cord results in: A. contralateral paralysis of the upper and lower extremities B. ipsilateral paralysis of the upper and lower extremities C. contralateral paralysis of the upper extremity only D. ipsilateral paralysis of the upper extremity only E. bilateral paralysis of the upper extremity

Answers: 1. A 2. D 3. D 4. B 5. B

Build-A-BrainStem Schofield THESE NOTES COVER 4 LECTURES: BRAINSTEM I-IV

LEARNING OBJECTIVES Upon mastering this material, the student will be able to: 1. Identify the major surface features of the brainstem in surface view and crosssections.

2. Describe landmark structures associated with different levels of the brainstem.

3. Relate nuclei and fiber tracts of the brainstem to the dorsal column/medial lemniscal system, anterolateral system and corticospinal system.

4. Describe the surface features and major lobes of the cerebellum.

5. Describe the cerebellar peduncles and how they attach the cerebellum to the brainstem.

6. Identify brainstem landmarks associated with modulation of movement.

7. Describe the locations and functions of the brainstem cranial nerve nuclei and their association with specific cranial nerves.

8. Describe the general location and extent of the brainstem reticular formation.

We will build a brainstem in several stages.

KEY TERMS (LISTED BY STAGE) Stage 1. Surface landmarks base base of pons central canal cerebral aqueduct cerebral peduncle closed medulla cranial nerves III-XII crus cerebri fourth ventricle

inferior cerebellar peduncle inferior colliculus middle cerebellar peduncle open medulla pyramid pyramidal decussation rhomboid fossa

Stage 2. The eight cross sections cochlear nuclei decussation of superior corticospinal tract cerebellar peduncle 1

substantia nigra superior cerebellar peduncle superior colliculus tectum tegmentum trochlear nerve

dorsal column nuclei facial nerve fibers

Build-A-BrainStem Schofield inferior olivary nucleus internal arcuate fibers medial lemniscus Stage 3. The pathways anterolateral system corticospinal pathway cuneate fasciculus cuneate nucleus Stage 4. The cerebellum accessory cuneate nucleus anterior lobe ataxia cerebellar cortex decussation of superior cerebellar peduncle deep nuclei flocculonodular lobe flocculus

periaqueductal gray red nucleus

transverse pontine fibers

dorsal column/medial lemniscal pathway fine touch gracile fasciculus gracile nucleus

internal arcuate fibers medial lemniscus pain pyramidal tract spinothalamic pathway

inferior cerebellar peduncle middle cerebellar peduncle nodule (nodulus) pontine nuclei pontocerebellar fibers posterior lobe posterior spinocerebellar tract

posterolateral fissure primary fissure red nucleus red nucleus restiform body superior cerebellar peduncle transverse pontine fibers white matter

Stage 5. Cranial nerve nuclei, by functional groups abducens nucleus general sensory branchial arch hypoglossal nucleus (pharyngeal arch) inferior salivatory branchial motor nucleus chief (or principal) mesencephalic sensory nucleus trigeminal nucleus cochlear nucleus nucleus ambiguus dorsal motor nucleus of oculomotor nucleus the vagus solitary nucleus Edinger-Westphal solitary tract nucleus somatic motor facial nucleus special sensory

spinal trigeminal nucleus spinal trigeminal tract superior salivatory nucleus trigeminal motor nucleus trochlear nucleus vestibular nuclei visceral motor (parasympathetic) visceral sensory

Stage 6. Reticular formation et al. inferior colliculus substantia nigra periaqueductal gray superior colliculus Image Acknowledgments: used, with permission, from: Purves, 6th Edition Haines Neuroanatomy Atlas in Clinical Context Netter Presenter Image Copyright 2003 Icon Learning Systems. All rights reserved.

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Build-A-BrainStem Schofield Medical Neuroscience AIMS materials (listed as “MN” or “NB Atlas”), copyright NEOMED. Additional images by BRSchofield, 2010-20.

Build-A-BrainStem, and BABS are copyright 2020, BRSchofield Outline Overview: Build-A-BrainStem Stage 1. Surface features and ventricular structures Key landmarks for medulla, pons and midbrain Ventricular landmarks Base, tegmentum and tectum Stage 2. The eight key cross sections Stage 3. The 3 main pathways Voluntary movement: the corticospinal pathway (pyramidal tract) Sensation: two pathways for fine touch and pain Fine touch: the dorsal column/medial lemniscal pathway Pain: the anterolateral system Stage 4. The cerebellum External features Cerebellar peduncles Internal structure Connections with brainstem structures Landmarks Medulla Pons Midbrain Clinical picture Stage 5. Cranial nerve nuclei Attachment points Functional components Somatic motor Branchial motor Visceral motor Special visceral Special sensory General sensory Stage 6. Reticular formation, et al.

Motor modulation superior colliculus substantia nigra Hearing: inferior colliculus Reticular Formation Review Questions 3

Build-A-BrainStem: Overview Schofield

Overview The brainstem is a complicated place, with components of different systems, and thus different functions, intermingled with one another. This includes both fiber tracts and nuclei. A key to understanding the functions of the brainstem, and the deficits experienced by patients with brainstem damage, is to develop a three dimensional appreciation for the brainstem and its multiple components. As with many aspects of anatomy, such an appreciation is facilitated by examining cross sections through the area of interest. Imaging methods such as MR and CT (magnetic resonance and computerized tomography imaging) provide cross sectional images, but they lack the resolution to distinguish many areas we need to understand. We will use images of classic myelin-stained sections that, while still falling short of identifying every structure of interest, provides us with the means to understand our patients.

Over the next several lectures, we will build a brainstem and attach the cerebellum We will study 8 key cross sections; these are not evenly spaced, but are selected to show key features. We will follow these steps: 1. Identify brainstem surface structures 2. Identify key landmarks for distinguishing medulla, pons and midbrain.

3. Identify the landmarks for the eight key sections 4. Add the three pathways a. corticospinal pathway (for voluntary movement) b. dorsal column/medial lemniscus (for fine touch) c. anterolateral system (pain perception) 5. Connect the cerebellum 6. Identify and localize the cranial nerve nuclei 7. Identify the reticular formation For the curious: In the end we will have 8 sections that proceed from caudal to rostral through the brainstem. It may seem weird at first, but we will not march through these sections in a nice orderly caudal to rostral order. Why not?! We will start with three sections that typify each brainstem subdivision and allow us to identify major landmarks.

We will then add the remaining sections, first for the medulla, then pons then midbrain.

Within each subdivision, we will start with the section we already saw (e.g. section 3 in mid-medulla) and then add the remaining sections as we identify additional distinguishing landmarks.

Throughout these lectures, the brainstem cross sections will have numbers (1-8, at lower left of each image) to help you learn the sections and put them in order (the numbers go from caudal to rostral). Please note: you will need to learn these sections without the numbers. You may see any of these schematics or images of the myelin-stained sections on an exam, but the numbers will not be included.

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Build-A-BrainStem: 1. Surface and Ventricles Schofield

Recall the first image below (from the Orientation lecture), then identify structures on the following image.

Examine the dorsal surface. Most of the cerebellum has been removed in order to visualize the dorsal surface of the brainstem. Note that the trochlear nerve attaches to the dorsal surface of the brainstem (then wraps around the brainstem to travel toward the orbit).

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Build-A-BrainStem: 1. Surface and Ventricles Schofield Now identify the structures visible on the ventral surface:

In the image above, the cranial nerves are listed on the right and other brainstem landmarks are listed on the left.

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Build-A-BrainStem: 1. Surface and Ventricles Schofield

Key landmarks for medulla, pons and midbrain Looking at the internal structure of the brainstem is essential for understanding its functional organization and therefore understanding patients with brainstem damage.

The surface structures provide reference points for relating individual cross sections with the major brainstem subdivisions.

On the ventral surface, take special note of three structures and their associated subdivision: • pyramid (and pyramidal decussation*): medulla • base of pons: pons • cerebral peduncle: midbrain * the pyramidal decussation is a large structure (as you will see later in the cross sections) but it is barely noticeable on the ventral surface (I’ve never seen it as clearly as it is drawn in the image above).

The cerebral peduncle. The cerebral peduncle contains the crus cerebri, a large bundle of fibers along the ventral surface of the brain, and a nucleus, the substantia nigra, located just dorsal to the crus cerebri. “Substantia nigra” means “black substance” and you will see in lab that it really is black in normal brains. (What about “abnormal” brains? Substantia nigra is the region that degenerates in Parkinson’s disease; this black area disappears in brains of Parkinson’s patients.)

So, technically, the “cerebral peduncle” refers to both the fiber bundle (crus cerebri) and the nucleus (substantia nigra). It is becoming common usage to refer to the crus cerebri as the cerebral peduncle; we want you to understand this and we will accept your referring to the fiber bundle as the crus cerebri or the cerebral peduncle.

In the myelin stains, remember that myelin wraps individual axons, so black marks fiber tracts; light areas are nuclei.

Use the structures at the base of the section to distinguish medulla, pons and midbrain.

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Build-A-BrainStem: 1. Surface and Ventricles Schofield

Base, tegmentum and tectum The area between the ventral surface and the ventricles can be further divided into a “base” along the ventral surface and a “tegmentum” that fills the space between the base and the ventricle. The tegmentum forms the core of the brainstem. The part of the brainstem dorsal to the ventricle is the “tectum”.

Recall that the cerebellum is not part of the brainstem, so the only part of the brainstem considered to have a tectum is the midbrain.

Also, note that the terms “tectum”, “tegmentum” and “base” are not usually applied to the caudal medulla. However, they are very useful for discussing the midbrain through the upper half of the medulla – the part associated with the fourth ventricle – and we will take advantage of their usefulness.

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Build-A-BrainStem: 1. Surface and Ventricles Schofield

base, tegmentum and tectum • tectum: only in midbrain • tegmentum: extends through brainstem • base: key to major subdivisions o pyramid: medulla o base of pons: pons o cerebral peduncle: midbrain At this point, you should be able to look at any of the three sections, in isolation (i.e., one at a time, without the numbers or the other sections present for comparison), and identify the landmarks in the base, the components of the ventricular system, and assign each section to medulla, pons or midbrain.

We used 3 levels, labeled 3, 6 and 7 in the diagram, to characterize the major brainstem subdivisions. In the Stage 2, we will add the additional sections you need to be able to integrate the structures essential for your understanding of the brainstem. Note that the sections are not evenly spaced; rather, they are chosen to highlight specific structures.

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Build-A-BrainStem: 1. Surface and Ventricles Schofield

The ventricular landmarks Look again at the midsagittal section and note ventricular system components. The midbrain has the cerebral aqueduct. The pons has the upper part of the fourth ventricle. The fourth ventricle continues caudally to overlap with the rostral part of the medulla. further caudally, the fourth ventricle narrows into the very tiny central canal that occupies the caudal medulla and continues into the spinal cord. The transition from fourth ventricle to central canal provides the basis for distinguishing the rostral “open medulla” from the caudal “closed medulla”.

• • • •

cerebral aqueduct: midbrain fourth ventricle: pons fourth ventricle: open medulla central canal: closed medulla

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield

Here is a list of the sections, arranged from caudal to rostral, with their distinguishing features: Medulla Closed medulla pyramid/pyramidal decussation central canal 1. Motor decussation pyramidal decussation 2. Sensory decussation internal arcuate fibers dorsal column nuclei medial lemniscus Open medulla fourth ventricle inferior olive 3. Middle medulla 4. Upper medulla cochlear nuclei Pons 5. Pons/medulla junction base of pons VII nerve fibers 6. Mid pons base of pons Midbrain 7. Lower midbrain inferior colliculus decussation of superior cerebellar peduncle 8. Upper midbrain: superior colliculus red nucleus

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield

Medulla The medulla is the most complicated of the regions. We have already distinguished Open vs. Closed, based on open fourth ventricle vs. central canal. Our Section 3, Mid medulla, is part of Open medulla; here we distinguish another section, Upper medulla, that includes the cochlear nuclei (key structures for hearing).

Sections 3 and 4 represent the open medulla:

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield Sections 1 and 2 represent the closed medulla:

Pons Sections through the pons are generally dominated by the overlying cerebellum and the middle cerebellar peduncle that connects the pons and cerebellum. We have already looked at Section 6, mid pons.

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield Mid pons (section 6) We now identify the two sets of fibers in the base of the pons. One set is made up of fibers running “across” the section, i.e., transversely.

These are the transverse pontine fibers (represented by the dashed lines). The second set of fibers is a bundle that runs through the brainstem longitudinally. It is in fact a continuation of the pyramids in the medulla (and the corticospinal tract in the spinal cord). Because its main component is the corticospinal tract, we will call this bundle the “corticospinal fibers in the pons”, or just “corticospinal fibers” (represented by the oblong gray shape in the schematic section).

Medulla-pons junction (section 5) Now we add Section 5, located at/near the junction of the medulla and pons.

Still have base of pons, with pontine nuclei, corticospinal fibers and transverse pontine fibers, as well as the fourth ventricle.

Key addition at medullapons junction: fibers of the facial nerve.

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield

Midbrain Sections through midbrain are typified by the cerebral peduncles in the base and a cerebral aqueduct. The cerebral aqueduct is surrounded by a conspicuous nucleus (light area in the myelin stain), call the periaqueductal gray. If you look at midsagittal or ventral views, you will also note that the midbrain’s neighbors, particularly the base of the pons at the caudal end and the diencephalon (thalamus and hypothalamus) at the rostral end, tend to crowd in on the midbrain territory. As a consequence, it is common to see some “bits” of the neighbors even in classic sections through the midbrain. Despite these complications, the landmarks we identify will provide you with solid guidance for identifying midbrain structures.

Lower midbrain (section 7) In fact, our Section 7 (see image at right) has clear cerebral peduncles, but on each side the ventral part of the cerebral peduncle has a bit of “base of pons” attached.

Accordingly, this cross section is from the lower midbrain (as indicated in the surface views).

We now add two key structures that characterize lower midbrain: • decussation of the superior cerebellar peduncle • inferior colliculus The decussation of the superior cerebellar peduncle is a fiber tract located in the tegmentum; since it is a decussation it (a crossing over of the midline), it spans the midline. Functionally, it is associated with the motor functions of the cerebellum (necessary for smooth, coordinated movements). The inferior colliculus forms the “roof” of the lower midbrain; i.e., it is part of the tectum. It is also part of the pathway for the sense of hearing.

Upper midbrain (section 8).

The upper midbrain contains the major midbrain landmarks: cerebral peduncle and cerebral aqueduct. Once again, there is a conspicuous periaqueductal gray. The decussation of the superior cerebellar peduncle disappears and the red nucleus appears in the tegmentum. The tectum at this level is made up of the superior colliculus (the layers of this structure can help you distinguish it from the inferior colliculus). The superior colliculus helps us direct our eyes toward an item of interest.

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield Here is a summary diagram of our 8 reference sections, with the structures we have identified so far.

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Build-A-BrainStem: 2. The Eight Cross Sections Schofield Here are the same sections as myelin stains; getting comfortable looking at these sections, and recognizing the key structures, is our ultimate goal here.

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Build-A-BrainStem: 3. The “Big Three” Pathways Schofield

We now have a framework of the brainstem with 8 cross sections to view the internal organization. Next, we will add the three pathways that we introduced earlier: 1. Corticospinal pathway: for voluntary movement 2. Dorsal column/medial lemniscus pathway: for fine touch 3. Anterolateral system: for pain We will take one pathway at a time and follow it through the brainstem. We will then examine the nature and distribution of the deficit we would expect if a patient has a lesion of that pathway.

Voluntary movement: The corticospinal pathway Striated muscles of the body and head over which we have voluntary control are innervated by neurons, called motor neurons, in the spinal cord (for most of the body muscles) and brainstem (via cranial nerves to head and some related muscles). Voluntary contraction of these muscles is controlled by neurons in the frontal lobe of the cerebral cortex. Axons of these neurons extend all the way from the cortex to the brainstem and spinal cord, where the motor neurons are located. Here, we will focus on the component that goes to the spinal cord, the aptly named corticospinal tract. (Of course, we also have voluntary control over the muscles innervated by cranial nerves; this control is handled by the “corticobulbar pathway”, so named because the brainstem was once referred to as the “bulb”).

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Build-A-BrainStem: 3. The “Big Three” Pathways Schofield Because the information (i.e., the nerve impulses and thus the command to move) travels from cortex to spinal cord, i.e., from top downward, we will follow the same route in tracing out the corticospinal pathway through the brainstem. Identifying this pathway in our eight cross sections will be easy because we have already identified almost all the key structures. As you recall from the Orientation lecture, the cerebrum is attached to the brainstem via the cerebral peduncles. The corticospinal fibers enter the brainstem as a central part of each cerebral peduncle. The axons eventually reach the spinal cord, where most of them end up in the lateral corticospinal tracts and a small percentage end up in the anterior corticospinal tracts. Because the corticospinal tract traverses the pyramids, it is often called the pyramidal tract.

Brainstem structures formed or traversed by the corticospinal pathway: • corticospinal fibers in the cerebral peduncle • corticospinal fibers in the base of the pons • pyramid • pyramidal decussation The corticospinal (pyramidal) tract in the cross sections of brainstem Here are the sections with the corticospinal components colored purple. They are in order from rostral (top left, section 8) to caudal (bottom right, section 1).

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Build-A-BrainStem: 3. The “Big Three” Pathways Schofield The clinical picture*. Damage to the corticospinal pathway leads to paralysis or, if the damage is restricted to a portion of the pathway, to weakness (called paresis). To understand the clinical picture, we can focus on the large component of the pathway that crosses the midline; i.e., called the lateral corticospinal tract in the spinal cord.

If there is damage in the spinal cord, the patient will be paralyzed on the same side as the lesion, and for all the muscles innervated from the lesion site and all lower sections of the spinal cord. So, a lesion in left thoracic spinal cord would cause left-sided (ipsilateral) paralysis of muscles in the lower half of the body (leg and lower trunk). If the lesion were higher, say lower cervical level, the deficit could include arm and upper trunk as well as leg and lower trunk. *the clinical picture is more complicated than we present here; for example, paralysis or paresis can result from damage to the motor neurons in the ventral horn of the spinal cord, with minimal or no damage to the corticospinal tracts. As the course progresses, you will learn to distinguish these possibilities. For now, the features that we mention, such as the side and body parts affected, are accurate and you will need to understand them.

The pyramidal decussation in the lower medulla is the point at which the pyramidal pathway crosses the midline. So, if the pyramid is lesioned in the right medulla, above the level of the decussation, all the fibers of the left lateral corticospinal tract would be lesioned and the patient would be paralyzed on the entire left side. This paralysis is now contralateral to the lesion, which was on the right side of the medulla.

Is it reasonable to imagine a lesion that damages one pyramid and not the other? (I mean, really, the left and right pyramids are adjacent to one another!) Yes, it does happen, because the blood supply tends to respect the midline. It is usual for a stroke to cause a lesion that has a (fairly) strict border along the midline.

If the corticospinal tract is damaged anywhere else along its path through the right side of the brainstem – i.e., in the base of the right pons or in the right cerebral peduncle – the deficit would be leftsided (contralateral) paralysis or paresis.

Finally, imagine that the lesion occurred exactly in the pyramidal decussation. Even if this lesion were located mostly on one side, it 20

Build-A-BrainStem: 3. The “Big Three” Pathways Schofield could catch some fibers before they’ve cross and some after they’ve crossed. Result: bilateral paralysis (i.e., quadriplegia).

Sensation: two pathways for fine touch and pain We introduced the dorsal column/medial lemniscal (DC/ML) pathway for fine touch and the anterolateral system (ALS) for pain in the Orientation to the Nervous System lecture, and you have seen their locations in the Spinal Cord.

Here, we will trace the two systems through the brainstem.

Once we have identified the structures associated with the two pathways, we will consider them from the clinical perspective.

Fine touch: the dorsal column/medial lemniscus pathway In the spinal cord, the DC/ML is represented by the dorsal columns, comprising the gracile fasciculus (aka, fasciculus gracilis) and the more laterally placed cuneate fasciculus (aka, fasciculus cuneatus).

Here is a list of the brainstem structures of the DC/ML pathway: a. b. c. d. e. f.

gracile fasciculus gracile nucleus cuneate fasciculus cuneate nucleus internal arcuate fibers medial lemniscus

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Build-A-BrainStem: 3. The “Big Three� Pathways Schofield The dorsal column/medial lemniscal system in the cross sections of brainstem

Here are our eight sections with DC/ML structures added in light blue. The sections are lined up as before, so if you want to follow the pathway from caudal to rostral, the way the sensory information flows, start at the bottom right and move up the column, then move to the middle column and then left column, moving up within each column.

The clinical picture.

The lesion depicted in the image is rather small (but not unrealistic). Imagine a stroke that caused a lesion that extended from the red X all the way to the ventral surface of the pons (also realistic), lesioning the corticospinal tract as well. You should expect deficits in both fine touch and voluntary movement, and those deficits would be seen contralateral to this stroke.

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Build-A-BrainStem: 3. The “Big Three” Pathways Schofield

The anterolateral system: pain Also frequently called the “spinothalamic pathway”.

Here are our eight cross sections with the anterolateral system added in green.

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Build-A-BrainStem: 3. The “Big Three” Pathways Schofield The clinical picture.

Again, the clinical picture is more complicated than we present here, and we will fill in more details as the course progresses. The key feature is for you to understand how the distribution and nature of deficits can be related to the location of a lesion. A lesion of the ALS in the brainstem is associated with loss of pain sensation on the contralateral side of the body.

This completes our “first pass” of identifying the structures of the three main pathways – for voluntary control of movement, perception of fine touch, and perception of pain – in cross sections of the brainstem. Some obvious, but important, considerations: all three pathways are found in every section. The location of each component is important, with special emphasis on proximity to the midline, because strokes commonly damage just the medial or just the lateral parts of the brainstem (we’ll get back to this, but take note that location is key to understanding brainstem strokes and, in some cases, can indicate whether a particular patient is facing an immediately lifethreatening situation).

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Build-A-BrainStem: 4. The Cerebellum Schofield

The cerebellum is essential for normal movement. It is not part of the brainstem but is closely attached to it, receiving inputs from several brainstem nuclei and sending projections to the brainstem (as well as higher levels). When the cerebellum is damaged, the result is uncoordinated movement clinically referred to as “ataxia”. We will have a detailed lecture on the cerebellum as part of a block of lectures on the motor systems. Now, we will get oriented to the major parts of the cerebellum, identify the cerebellar peduncles (the large fiber bundles that attach the cerebellum to the rest of the brain), and identify the associated fiber tracts and nuclei in the brainstem. Finally, we will consider a brief overview of cerebellar function as revealed by the deficits that appear when the cerebellum or its connections are lesioned.

EXTERNAL FEATURES The surface of the cerebellum includes many thin folds of tissue separated by grooves.

In the cerebellum, the folds are called “folia” (singular: folium) and the grooves are called sulci. A few of the sulci are particularly deep, and are relevant because they divide the cerebellum into different functional lobes. These deeper sulci are called fissures; we will identify two of them: the primary fissure and the posterolateral (or dorsolateral) fissure. Despite its name, the “primary” fissure is not particularly distinguishable from the surface, so we will use the midsagittal view to identify this fissure.

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Build-A-BrainStem: 4. The Cerebellum Schofield

Gross anatomy Three main lobes 1. Anterior lobe -----Primary fissure 2. Posterior lobe -----Posterolateral fissure 3. Flocculonodular lobe The primary fissure separates anterior and posterior lobes. The posterolateral fissure (also known as dorsolateral fissure) separates the posterior lobe from the flocculonodular lobe.

The flocculonodular lobe comprises a single nodule (or nodulus) on the midline and two flocculi (singular: flocculus), one on each side.

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Build-A-BrainStem: 4. The Cerebellum Schofield THE CEREBELLAR PEDUNCLES The picture shows a posterior view of a brain in which most of the cerebellum has been removed. The cerebellar peduncles (peduncle = stalk) are labeled on the left side.

The image shows a phantom view to help you visualize the main course of the fiber bundles that make up the cerebellar peduncles.

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Build-A-BrainStem: 4. The Cerebellum Schofield INTERNAL STRUCTURE OF THE CEREBELLUM The cerebellum includes a cortex on the surface, white matter and deep nuclei.

Cerebellar cortex, which is gray matter, has several layers of neurons. The underlying white matter is made up of myelinated axons traveling to and from the cerebellar cortex. The deep nuclei (gray matter again, made up of neurons) are the major source of output from the cerebellum.

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Build-A-BrainStem: 4. The Cerebellum Schofield The cerebellar connections in the cross sections of brainstem Numerous brainstem structures are closely related to the cerebellum; conveniently, we have already identified some of them as landmarks in our cross sections (highlighted here in yellow). In addition, part of the cerebellum itself is visible, in Sections 5 and 6 (shaded light yellow).

Note that the transverse pontine fibers -- the dashed black lines that we identified in the base of the pons -- are among the components with close association with the cerebellum.

Also, we now acknowledge that our “lower midbrain� section has a little bit of pons still attached to it: the pontine nuclei and some transverse pontine fibers are attached to the ventral edge of the cerebral peduncle.

A number of additional structures, mostly fiber tracts, are related to the cerebellar peduncles. We will consider these one brainstem subdivision at a time because, for the most part, this follows the components of the three cerebellar peduncles.

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Build-A-BrainStem: 4. The Cerebellum Schofield Cerebellar structures in the medulla (associated with inferior cerebellar peduncle)

The restiform body forms the bulk of the inferior cerebellar peduncle. It carries many fibers from the spinal cord into the cerebellum (including fibers from the posterior spinocerebellar tract). It has other components that we will cover in later lectures.

We have also added the accessory cuneate nucleus (aka lateral cuneate nu.; external cuneate nu.). This is different from the cuneate nucleus of the DC/ML system.

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Build-A-BrainStem: 4. The Cerebellum Schofield Cerebellar structures in the pons (associated with middle cerebellar peduncle) The base of the pons has two major components directly tied to the cerebellum. The pontine nuclei are neurons whose axons project across the midline and into the cerebellum. We have already identified these axon bundles as the transverse pontine fibers. Given that these axons originate in the pons and terminate in the cerebellum, you can understand why they are also called pontocerebellar fibers. Note how the transverse orientation of these fibers is perpendicular to the corticospinal fibers that are traveling through the base of the pons on their way to the spinal cord. The corticospinal fibers are oriented longitudinally. Returning to the transverse pontine fibers, as they approach the lateral edge of the pons, they coalesce to form the middle cerebellar peduncle, which you can follow all the way into the cerebellum .

In addition to the structures just discussed, Section 5 through the lower pons allows us to identify a fiber bundle that we saw in the medulla: the restiform body has entered the cerebellum, but is still distinguishable as a bundle of fibers.

Note also that in both sections, “buried� within the cerebellum, is the origin of the superior cerebellar peduncle (which we will cover next as associated with the midbrain). This pathway originates in the cerebellum, and is distinguishable here before it leaves the cerebellum to ascend into the midbrain.

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Build-A-BrainStem: 4. The Cerebellum Schofield Cerebellar structures in the midbrain (associated with superior cerebellar peduncle)

The red nucleus, of the upper midbrain, and the decussation of the superior cerebellar peduncle are two key midbrain structures associated with the cerebellum.

In addition, many fibers of the crus cerebri (cerebral peduncle) are closely related to the cerebellum. These fibers originate in widespread areas of cerebral cortex, and terminate in the pontine nuclei (thus they are called corticopontine fibers). They don’t travel directly to the cerebellum, but their termination in the pontine nuclei ties them directly to cerebellar circuits. For this reason, we have labeled the crus cerebri, minus the corticospinal fibers, as cerebellar-related (yellow shading).

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Build-A-BrainStem: 4. The Cerebellum Schofield Cerebellum: Clinical perspective Lesion of the cerebellum leads to uncoordinated “ataxic� movement. This is distinctly different from the deficits associated with lesion of the corticospinal system (paralysis or paresis).

Also, damage to one side of the cerebellum leads to IPSILATERAL ataxia. The right side of the cerebellum is concerned with the right side of the body; left side with left side of body.

So, the brainstem includes two large structures, the inferior olivary nucleus and the red nucleus, that we associated with the cerebellum and yet we did not see direct connections among these structures. We will see in future lectures that these structures are interconnected; for now, you should associate these nuclei with the cerebellum and understand that damage to these structures could cause ataxia.

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield

You have studied the peripheral distributions, targets and functions of the cranial nerves in previous courses.

Here, we will see how the sensory information in those nerves is distributed to appropriate places in the brainstem, and how particular brainstem nuclei provide the autonomic and motor commands for muscles and glands.

For review. (I will not go over this in lecture; we will assume you have already mastered most of the information in this chart. We will consider functions in more detail as the course progresses).

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield We will: 1. review the locations where cranial nerves attach to the brainstem 2. review the functional components of the cranial nerves 3. identify the brainstem nuclei associated with the different functional components Attachment points of the brainstem cranial nerves First, we will review the attachment points of the cranial nerves with the brainstem.

Knowing these locations will be important for later understanding of the ways in which different functional components (e.g., pain vs. fine touch) of a nerve connect with their associated brainstem nuclei. In some cases, axons must travel a substantial distance through the brainstem to bridge the gap between the relevant brainstem nucleus and the point where the nerve attaches to the brainstem. For example, pain fibers in the trigeminal nerve attach to the middle of the pons but must reach their target nucleus in the medulla.

The functional components of the brainstem cranial nerves Below is a table modified from the Human Structure course, summarizing the cranial nerves and their major components. Note that “pharyngeal arch” = “branchial arch” in

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield these discussions. The “Embryonic Region” column is for your reference/recollection (we will not be addressing these details directly in Medical Neuroscience).

Note some distinctions. First, MOTOR (efferent) vs. SENSORY (afferent). These two broad categories can be subdivided according to function: MOTOR • Somatic motor (innervating striated muscles) • Branchial motor (developed from branchial arches) • Visceral motor = autonomic (= parasympathetic, since we’re in the brainstem).

SENSORY • General sensory (i.e., fine touch, pain; the “head” equivalents of the DC/ML system and the ALS system that carries similar information from the body) • Visceral sensory (this includes general sensations such as pain as well as information from, e.g., the carotid body.) In addition, it includes the “special visceral” sensation of taste.

• Special sensory (for brainstem, this includes hearing and balance. Note that smell and sight, with cranial nerves I and II, are also special senses, but are not covered here because they don’t attach to the brainstem).

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield

One consequence of the relationships described above is that there is sometimes, but not always, a simple one-to-one relationship between a cranial nerve and a brainstem nucleus. Nerves IV, VI and XII, which are “purely” somatic motor, are each associated with a single nucleus. At the other end of the spectrum, nerves associated with the branchial arches have multiple functional components and thus are connected with multiple brainstem nuclei.

The cranial nerve nuclei are distributed among all three brainstem subdivisions (medulla, pons, midbrain). These nuclei are located in the tegmentum (not the base or the tectum); looking at our last set of sections, you will see that much of the tegmentum (red outlines in our schematics) is currently “undefined” (i.e., shaded gray).

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield Another important point is that, to a large extent, the fibers traveling between a nucleus and the attachment point of a cranial nerve follow a relatively direct path from the one to the other. Why do we discuss this? First, deficits can arise whether the nucleus or the connecting fibers are damaged, and numerous clinical syndromes can be understood only by recognizing this fact and understanding where the fibers travel. Second, in some cases, the fibers must travel a substantial distance within the brainstem before they reach their target nucleus. Again, this can have important clinical implications. We will cover those points that are important for the clinical issues we will encounter later in the course.

Somatic motor nuclei

(same chart as in slide; reprinted here to make easier to read) Innervation III Oculomotor IV Trochlear VI Abducens

most eye muscles superior oblique lateral rectus

XII Hypoglossal

tongue

Brainstem nucleus oculomotor nucleus trochlear nucleus abducens nucleus hypoglossal nucleus

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Level

Sections

upper midbrain

8

lower midbrain Medulla-pons junction medulla (closed and mid)

7 5 2-3

Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield Note the four nuclei. Three of the nerves are also located. The trochlear nerve is not visible here; it is “odd� in two ways. First, it exits the dorsal surface (unlike any other cranial nerve). Second, it crosses the midline, within the brainstem, so that the right trochlear nucleus gives rise to the left trochlear nerve. This has minimal impact clinically because most lesions that affect trochlear function do so by damaging the peripheral part of the nerve (the nerve is very thin, but it has the greatest intracranial length of any cranial nerve because it has to circle around the brainstem before exiting the cranial cavity. Lesion of the trochlear nucleus would cause a contralateral deficit, but in practice most trochlear problems affect the nerve and thus are ipsilateral to the lesion.

Visceral motor nuclei = autonomic: parasympathetic

(table duplicated on next page for readability)

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield Innervation III Oculomotor VII Facial IX Glossopharyngeal X Vagus

ciliary mus.; sphincter pupillae most salivary glands, lacrimal parotid most of viscera

Brainstem nucleus EdingerWestphal nucleus superior salivatory nucleus inferior salivatory nucleus dorsal motor nucleus of vagus

Level

Brainstem nucleus trigeminal motor nucleus facial nucleus

Level

Sections

upper midbrain

8

medulla-pons junction

5

upper medulla

4

medulla (closed and mid)

2-3

Branchial motor nuclei

(table duplicated for readability) Innervation V Trigeminal

mastication

VII Facial

facial expression

IX Glossopharyngeal X Vagus

stylopharyngeus pharynx, larynx

nucleus ambiguus

upper midbrain

6

medulla-pons junction

5

most of medulla

40

Sections

2-4

Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield Special sensory nuclei

(again, table duplicated for readability) Innervation cochlea VIII Vestibulocochlear

vestibular apparatus

Brainstem nucleus cochlear nucleus

Level upper medulla

4

vestibular nuclei

open medulla lower pons

3-5

41

Sections

Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield Visceral sensory nuclei

(again, table duplicated for readability) Innervation VII Facial IX Glossopharyngeal X Vagus

anterior 2/3 of tongue post. 1/3 tongue

Brainstem nucleus

Level

Sections

solitary nucleus

most of medulla

2-4

pharynx, larynx

Note that the solitary nucleus has a fiber bundle running down the middle of the nucleus. This fiber bundle carries the incoming sensory fibers as they travel to the appropriate part of the solitary nucleus.

This arrangement produces a distinctive appearance in the myelin stains: a dark center surrounded by the light-colored ring.

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield General sensory nuclei Innervation V Trigeminal VII Facial IX Glossopharyngeal X Vagus

face, oral cavity ear canal, nearby skin, post 1/3 tongue; ear ear canal, nearby skin, pharynx

Brainstem nucleus Trigeminal Chief sensory nu.

Mesencephalic V nu.

Spinal V nu.

Level

Sections

mid pons midbrain medulla, lower pons

1-8

Note that general sensory fibers arrive from cranial nerves V, VII, IX and X; these general sensory fibers travel to nuclei with “trigeminal” in the name. The majority of the sensory fibers are from the V nerve, but the point is that nerve is not equivalent to nucleus (i.e., the spinal trigeminal nucleus receives sensory fibers from cranial nerves V, VII, IX and X). To say “the trigeminal nucleus” is insufficient.

When it comes to naming,

nerve ≠ nucleus

You MUST be careful when you refer to the name of any of these nuclei.

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Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield

Another factor complicating the trigeminal nuclear complex is that the nerves that feed into them – V, VII, IX and X – attach at various points along the brainstem, but the trigeminal nuclear complex extends from the midbrain to the spinal cord. Consequently, many fibers have to travel from their attachment point up into the midbrain or down into the medulla to reach their appropriate targets. These fibers form distinct bundles. The mesencephalic trigeminal nucleus is rather small, so the fiber bundles associated with it, the mesencephalic trigeminal tract, are also small and tend to mix in with the nucleus. However, there are many fibers traveling to the caudal part of the spinal trigeminal nucleus, so there is a large fiber bundle called the spinal trigeminal tract.

This tract is especially important clinically because it is carrying all the pain information from the face and most of the head (including the meninges, which are associated with vascular headache pain). The spinal trigeminal tract is located just lateral to the spinal trigeminal nucleus. You will need to distinguish these structures functionally and identify them in the myelin stains.

44

Build-A-BrainStem: 5. Cranial Nerve Nuclei Schofield

45

Build-A-BrainStem: 6. Reticular formation et al.

Schofield

We have only a few more regions to identify in the brainstem, several of which were included in our landmarks. We return to them now to add more functional context.

MOTOR MODULATION Two areas in the midbrain play important roles in the control of movement.

Substantia nigra: functionally a part of the socalled “basal ganglia�, which are structures in the forebrain that you will identify in upcoming lectures. The substantia nigra plays a key role in most movements.

Degeneration in this nucleus is associated with Parkinson’s disease.

Damage to the substantia nigra does NOT lead to the paralysis associated with corticospinal damage, or the ataxia associated with cerebellar damage, but to other motor deficits (e.g., slow movements, difficulty starting and stopping movements). At this point, you can see that there are many regions of the brainstem for which a lesion would cause motor deficits; the detailed nature of these deficits will be determined by which components of the motor system are damaged.

46

Build-A-BrainStem: 6. Reticular formation et al.

Schofield Superior colliculus: another structure involved in the motor system. The superior colliculus is responsible for turning our eyes (and head, if necessary) to allow us to look at an item of interest.

Damage to the superior colliculus leads to deficits in eye movements.

HEARING Two landmarks that we identified earlier are components of the neural pathway for the sense of hearing: the cochlear nucleus, in the upper medulla, and the inferior colliculus, in the lower midbrain. The cochlear nucleus is a direct target of fibers originating in the cochlea and travelling in cranial nerve VIII (so these nuclei are already labeled “special sensory� in our schematics). We now identify the inferior colliculus as a key link in the auditory pathway. Even though the inferior colliculus is not a direct target of the VIII nerve, we will give it the peach-colored shading to associate it with special senses.

47

Build-A-BrainStem: 6. Reticular formation et al.

Schofield RETICULAR FORMATION The reticular formation extends through the length of the brainstem, largely filling the tegmentum. It comprises many nuclei, some of which are well-defined (e.g., they are a compact group of neurons that all use acetylcholine as a neurotransmitter). In fact, one part of the reticular formation was already identified in the midbrain: the periaqueductal gray. As its name implies, it is gray matter that surrounds the cerebral aqueduct. One important function of the periaqueductal gray is suppression of pain.

Other nuclei of the reticular formation are less well-defined in that they don’t have easily recognized borders; a region that serves one function may overlap with a region that serves a different function. You will learn a few of these areas, sometimes with discrete names for the nuclei (e.g., the locus coeruleus) and sometimes with only a vague description (e.g., pontine reticular formation). Here, we update our schematic sections, with broad identification of the reticular formation, now labeled in brown.

48

Build-A-BrainStem: 6. Reticular formation et al.

Schofield (table duplicated for readability) Review the partial list of functions and you can see how damage in the reticular formation can have many consequences, including coma or death.

• • • • • • • • • •

control of sleep and wakefulness cardiac function breathing setting of muscle tone autonomic tone reflexes associated with the cranial nerves vomiting bladder control suppression of pain and others

When you look at the myelin sections in lab, you will note that much of the territory of the reticular formation is darkly stained, indicating many myelinated fibers. We have traced a few cranial nerve fibers through what we now label as reticular formation. There are additional pathways that also traverse this region. We will name just a couple of those pathways later in the course; even then, we will localize them only loosely (e.g., “in the lateral reticular formation, or “lateral tegmentum”).

49

Build-A-BrainStem: Review Questions Schofield REVIEW QUESTIONS 1. The crus cerebri is a component of which CNS subdivision? a. diencephalon b. medulla c. midbrain d. pons e. spinal cord 2. Which cranial nerve(s) attach to the middle of the pons?

3. The hypoglossal nerve attaches to the brain between which two surface structures? a. inferior colliculus and cerebellum b. left and right cerebral peduncles c. olive and cerebellum d. pyramid and olive e. pyramid and pyramidal decussation 4. The pyramidal tract crosses the midline at which level? a. closed medulla b. lower midbrain c. mid pons d. open medulla e. upper midbrain 5. Cranial nerve nuclei are located in the (choose all that apply): a. base b. tectum c. tegmentum 6. The inferior colliculi are associated with the a. closed medulla b. lower midbrain c. mid pons d. open medulla e. upper midbrain 7. Damage to which structure would most likely cause loss of fine touch? a. anterolateral tract b. crus cerebri c. medial lemniscus d. pyramid e. substantia nigra 8. The cerebellum communicates with the medulla primarily via the a. cerebral peduncle b. inferior cerebellar peduncle c. middle cerebellar peduncle d. superior cerebellar peduncle

50

Build-A-BrainStem: Review Questions Schofield 9. Which of the following are closely associated with (i.e., connected to) the cerebellum (choose all that apply): a. gracile nucleus b. inferior colliculus c. inferior olivary nucleus d. internal arcuate fibers e. periaqueductal gray f. pontine nuclei g. pyramidal decussation h. red nucleus i. restiform body 10. Damage to the cerebellum on the right side typically causes (pick one: ATAXIA or PARALYSIS) that affects movement on the (RIGHT or LEFT) side of the body.

11. Which brainstem nucleus controls the muscles of facial expression?

12. Which brainstem nucleus receives all visceral sensory inputs? In which brainstem subdivision is this nucleus located?

13. Which nucleus serves as the main source of parasympathetic fibers in cranial nerve X: a. dorsal motor nucleus of the vagus b. Edinger-Westphal nucleus c. nucleus ambiguus d. solitary nucleus e. trigeminal motor nucleus 14. Fibers carrying pain information from the face travel in which of the following structures (pick all that apply): a. medial lemniscus b. mesencephalic trigeminal tract c. motor trigeminal tract d. spinal trigeminal tract e. trigeminal nerve 15. The chief sensory nucleus is located at which brainstem level: a. medulla-pons junction b. mid-pons c. pyramidal decussation d. sensory decussation e. upper midbrain There are, of course, many more questions that could arise from the BABS lectures. In fact, the laboratory exercises, and the associated practical exam, will cover many of these topics. The questions above are not meant to be exhaustive, but to give you an idea of how such questions can be formulated. “Lab� questions, on a quiz or a lab practical exam, could include images of sections (myelin-stained or schematics).

51

Diencephalon-Mellott

Diencephalon Jeffrey G. Mellott, Ph.D. Learning Objectives: To summarize the basic gross anatomical and microanatomical organization of the diencephalic nuclei and their general functions and arterial blood supply.

1. Describe the anatomical position of the diencephalon and its relationship to proximal structures.

2. Identify and describe the location of the four regions of the diencephalon: a) dorsal thalamus b) hypothalamus c) epithalamus d) ventral thalamus 3. List the general functions of the four regions.

4. Describe the basic blood supply to the diencephalon.

Outline: Anatomical position of the diencephalon and neighboring structures. Major subdivisions of the diencephalon and their general functions.

A. Nuclei: I. Dorsal thalamus (commonly referred to as “thalamus�) a. anterior thalamic nuclei (anterior nucleus) b. medial thalamic nuclei (dorsomedial nucleus) c. lateral thalamic nuclei: i. nuclei of the dorsal tier (lateral dorsal, lateral posterior, pulvinar) ii. nuclei of the ventral tier (ventral anterior, ventral lateral, ventral posterior lateral and medial nuclei) iii. lateral geniculate body and medial geniculate body d. intralaminar thalamic nuclei (discontinuous groups of neurons embedded within the internal medullary lamina) II. Hypothalamus III. Epithalamus a. pineal gland b. habenular nuclei c. stria medularis thalami IV. Ventral thalamus (subthalamic nucleus) B. Blood supply of the diencephalon C. Clinical correlations D. Internal capsule

1

Diencephalon-Mellott

Diencephalon The diencephalon is one of two large regions that comprise the forebrain. The four principal subdivisions are the thalamus, hypothalamus, epithalamus and ventral thalamus.

Basic Organization: The diencephalon, positioned between the brainstem and telencephalon, consists of two symmetric halves separated by the space of the third ventricle. At the midline, the junction between the diencephalon and midbrain lies along a line extending from the caudal edge of the mammillary body to the posterior commissure. The boundary between the diencephalon and the telencephalon is less distinct. Laterally, the internal capsule separates the diencephalon from the telencephalon. Rostrally, the diencephalon is separated from the telencephalon by the collection of the interventricular foramen, the lamina terminalis and the optic chiasm.

The figure above is a midsaggital section through the diencephalon. Left is rostral; right is caudal; up is dorsal; down is ventral.

General function: The diencephalon is the main processing center for ascending sensory information (except olfaction) destined to reach the cerebral cortex.

2

Diencephalon-Mellott

A. Nuclei I. Dorsal thalamus (or thalamus): is a large collection of nuclei that serve in sensory, motor and limbic systems. The thalamus is often regarded as a functional “gateway” as nearly all information that reaches the cerebral cortex passes through the thalamus. Most regions of cerebral cortex give rise to reciprocal projections that target the thalamic nuclei from which they receive input.

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.87.6

3

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.I.33 General structural organization: The thalamus is covered and subdivided by thin sheets of myelinated axons. The axons that cover the lateral portions of the thalamus are known as the external medullary lamina. The axons that are found within the thalamus and thus subdividing the thalamus are known as the internal medullary lamina. These subdivisions are the anterior, medial and lateral thalamic nuclei.

4

Diencephalon-Mellott A. Anterior thalamic nuclei: Consists primarily of a large principal nucleus (anterior nucleus) that receives and sends information tied to the limbic systems.

B. Medial thalamic nuclei: The nucleus of interest is the mediodorsal (a.k.a. dorsomedial; a.k.a. medial dorsal) nucleus. The mediodorsal nucleus is commonly associated with pathways involving mood, personality, emotion and eye movement.

C. Lateral thalamic nuclei: group of nuclei that are separated into dorsal and ventral tiers.

i)

dorsal tier: a. lateral dorsal (LD) b. lateral posterior (LP) c. pulvinar-associated with eye movement, movement in the visual field and “attention� to the visual field

ii)

ventral tier: a. ventral anterior (VA)-motor b. ventral lateral (VL)-motor c. ventral posterolateral (VPL)-somatosensory d. ventral posteromedial (VPM)-somatosensory e. lateral geniculate nucleus (LGN)-vision f. medial geniculate body (MGB)-auditory

5

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.II.84/I.33.

The nuclei will be addressed in more detail regarding their functions, inputs and outputs in upcoming lectures.

Let us take a brief walkthrough the diencephalon.

6

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.88.4 The figure above (88.4) shows a coronal section through the level of the hypothalamus. Notice how the hypothalamus is anterior to the thalamus.

7

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig. 88.6 The figure above (88.6) shows a coronal section through the thalamus. Notice how you can see the anterior and medial dorsal thalamus.

8

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig. 87.7 The figure above (87.7) shows a horizontal section through the thalamus. Notice at this level you can identify the lateral, medial and anterior thalamic nuclei groups.

9

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig. 87.6 The figure above (87.6) shows a horizontal section through the level of the thalamus inferior to figure 87.7. Notice how the third ventricle is now present and the general position of the thalamus.

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Diencephalon-Mellott II. Hypothalamus: collection of nuclei that regulate homeostatic functions via the autonomic nervous system and endocrine activities.

The hypothalamus can be found 1) rostroventral to the thalamus (the hypothalamic sulcus separates the hypothalamus and thalamus); 2) lateral to the third ventricle; 3) dorsal to the pituitary; 4) rostral to the ventral thalamus and midbrain tegmentum; and 5) roughly by the “triangle� formed between the optic chiasm, mammillary bodies (part of hypothalamus) and the anterior commissure.

11

Diencephalon-Mellott General structural organization: the hypothalamus is a small region in the diencephalon that contains numerous functionally distinct nuclei.

The figure above gives you the stereotypical view of the hypothalamus. Some of the individual nuclei will be addressed in later lectures regarding their specific functions. Your goal from this lecture is to learn where the hypothalamus is located and use that knowledge in the laboratory in order to identify the hypothalamus in the wet brain and myelin stain preparations.

Comparison of Hypothalamus Coronal Sections at 3 Different Positions Anterior commissure

1. Take note of the size and shape of the 3rd ventricle.

2. In the more anterior sections (A, B) the optic tracts are visible.

3. In the posterior section, the large mammillary bodies are visible.

4. In section B – the fornix is seen bisecting the hypothalamus. * The areas outlined in black represent specific nuclei.

1.

2.

1.

Fornix 4.

2.

1.

3.

III. Epithalamus: Small collection of structures that occupy the dorsocaudal diencephalon. The principal structures in the epithalamus are the pineal gland, the habenula and the stria medullaris thalami.

General structural organization: The prominent nuclei of the epithalamus, the pineal gland and the habenula, reside near the midline and in the caudal region of the diencephalon. The habenula is anterior to the pineal. The pineal is unique in that the entire structure is made up of glial cells, no neurons are found in the pineal. The stria medullaris thalami is a fiber tract located on the dorsomedial aspect of the dorsal thalamus.

12

Diencephalon-Mellott A. Pineal gland: production of melatonin B. Habenula nuclei: limbic-motivational control of behavior IV. Ventral thalamus: For the purpose of this lecture, our focus of the ventral thalamus will be limited to the subthalamic nucleus.

General structural organization: The subthalamus is located posterior to the hypothalamus.

In the laboratory, you will identify the subthalamic nucleus most readily on coronal slabs. The subthalamus is involved in movement and associated with the basal ganglia.

13

Diencephalon-Mellott

B. Blood supply of the diencephalon Small branches of the great arterial circle (of Willis) and larger branches of the posterior cerebral artery provide blood supply to the diencephalon.

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.I.50A. The figure above (I.50A) shows a view of the great arterial circle. Notice the small arteries that branch off from the circle. Many of which will supply the diencephalon. Top-anterior; bottomposterior.

14

Diencephalon-Mellott

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.I.50B The figure above (I.50B) shows the great arterial circle as it supplies the ventral base of the diencephalon. Notice the pituitary and the relationship to the optic chiasm. Top-anterior; bottomposterior.

15

Diencephalon-Mellott

Blood Vessel Internal carotid arteries

Branches to the Diencephalon Ant. choroidal aa.

Anterior cerebral arteries (A1 segment)

Penetrating branchesĂ Ant. perforating substance Recurrent a. of Heubner

Middle cerebral arteries Posterior cerebral arteries (from Basilar a.)

Lat./Med. lenticulostriate aa.

Post. choroidal aa.

Thalamogeniculate aa.

Thalamoperforator aa.

C. Clinical correlations Strokes involving branches of the thalamogeniculate artery produce severe symptoms such as: Loss of sensory relay (hemianesthesia) through the ventral posterior (VPL/VPM) nuclei.

Strokes present a general but important observation: Many of the narrow arteries, such as the thalamogeniculate arteries, that supply the dorsal thalamus come off a very large parent artery. Thus, a floating piece of debris, such as a clot, may not be large enough to block the parent artery but will easily block a small artery that arises from the parent artery.

16

Diencephalon-Mellott

D. Internal capsule The internal capsule is not part of the diencephalon however; this is a good transition for the telencephalon lecture as the internal capsule is the fiber tract that connects the dorsal thalamus to the cerebral cortex. The internal capsule also consists of fibers that connect the cerebral cortex with the brainstem and spinal cord.

Netter’s Atlas of Human Neuroscience, 1st edition, Fig. on the page 184.

The internal capsule has five regions: anterior limb, genu and posterior limb, sublenticular limb (not shown in above figure) and retrolenticular limb (not shown in above figure). The structural organization and function of the internal capsule will be covered in tomorrow’s lecture. Notice the internal capsule’s position to the thalamus. The internal capsule is located laterally to the thalamus and provides as a very useful landmark when you are in the laboratory.

17

Diencephalon-Mellott

Self test questions: 1) Somatosensation in the dorsal thalamus is primarily processed by the: a. mediodorsal nuclei b. habenula c. ventral anterior nucleus d. ventral posterolateral nucleus 2) Which statements are TRUE? a. The pulvinar is posterior to the lateral dorsal nucleus of the dorsal thalamus. b. The mediodorsal nuclei mediate vision from the retina. c. The subthalamic nucleus is in the ventral thalamus d. The anterior thalamic nuclei process limbic signals. e. The medial geniculate body processes auditory signals. f. The hypothalamus is located caudally to the tegmentum. g. The 4th ventricle lines the medial wall of the diencephalon. h. The pineal gland is part of the epithalamus.

3) The dorsal thalamus receives blood flow primarily from the: a. Middle cerebral artery b. Posterior cerebral artery c. Anterior cerebral artery d. Lenticulostriate artery 4) Name three fiber tracts that you might likely observe coursing near or within the hypothalamus in a coronal view.

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Telencephalon Jeffrey G. Mellott, Ph.D. Learning Objectives: To summarize the basic gross anatomical and microanatomical organization of the telencephalon and describe general functions and arterial blood supply.

1. Describe the boundaries between the four lobes of the cerebral cortex and correlate each lobe with its major functions.

2. Understand the general organization and functions of the subcortical white matter.

3. Understand the general organization and functions of the basal ganglia.

4. Understand the general organization and major functions of the hippocampal formation.

5. Identify the location and primary function of the amygdala.

6. Identify the location and primary function of the claustrum.

7. Describe the basic blood supply to the telencephalon.

Outline: Anatomical positions of the telencephalon. Major subdivisions of the telencephalon and their general functions.

I. Cerebral cortex: lamination and lobes A. frontal lobe B. parietal lobe C. occipital lobe D. temporal lobe II. Subcortical white matter A. projection fibers-internal capsule i. genu ii. anterior limb iii. posterior limb iv. sublenticular limb v. retrolenticular limb B. commissural fibers i. corpus callosum ii. anterior commissure iii. posterior commisure C. association fibers III. Basal ganglia A. caudate nucleus i. head ii. tail B. putamen C. globus pallidus i. internal (medial)

1

ii. external (lateral) IV. Hippocampus V. Amygdala VI. Claustrum VII. Blood supply of the telencephalon VIII. Views of internal structure

Telencephalon The telencephalon is commonly the most recognizable region of the brain due to the two large hemispheres of cerebral cortex (gray matter). A deep fissure called the longitudinal fissure separates these hemispheres. The groove (gyrus) and valley (sulcus/fissure) appearance of the cerebral cortex occurs as the cortex folds on itself to allow for more surface area without the demand of increased volume. Deep to the cerebral cortex is an expansive region of subcortical white matter that carries neural connections to and from cortex. Buried in the telencephalon are structures with various functions: 1) the basal ganglia (motor function), 2) the hippocampus (memory), 3) the amygdala (emotions) and 4) the claustrum (consciousness).

A. Cerebral cortex General structural organization-lamination: The cerebral cortex is the major brain area associated with perception, consciousness and higher thought. Almost the entire surface of the cerebral hemisphere is covered by neurons that form layers parallel to the cortical surface. Such a layered structure is called a cortex. In most areas, the neurons form 6 layers and the general structure is known as neocortex. The "folded" nature of the cerebrum maximizes the amount of neocortex, which is a major factor distinguishing the human brain from other species. Some much more restricted areas of cerebral cortex contain 3 layers of cells, and are known as archicortex (in the hippocampus) or paleocortex (associated with olfaction).

Neocortex can be further subdivided according to differences in the cortical layers (thickness, cell types and size, etc‌). These differences allowed Brodmann to distinguish regions that also have distinct functions.

2

General structural organization-lobes: There are four lobes of cortex. The frontal lobe is at the most frontal/anterior position of the telencephalon. The occipital is at the most posterior position of the telencephalon. The parietal lobe is between the frontal and occipital lobes, at the dorsal aspect of the telencephalon. The temporal lobe is at the ventral base of the telencephalon.

3

I. Frontal lobe: a. contains precentral gyrus/primary motor cortex/Brodmann area 4 b. a few of the many functions associated with the frontal lobe i. motor ii. speech production iii. executive functions (judgment, planning problem-solving) II. Parietal lobe: a. contains postcentral gyrus/primary somatosensory cortex/Brodmann 3,1,2 b. a few of the many functions associated with the parietal lobe i. somatosensation ii. high-level visual processing

4

iii. sensory integration (e.g., integrate vision and somatosensation to understand where our body is located relative to things in our environment) iv. attention III. Occipital lobe: visual processing; primary visual cortex/Brodmann 17 IV. Temporal lobe: a. contains the primary auditory cortex/Brodmann 41 b. a few of the many functions associated with the temporal lobe i. audition ii. high-level visual processing iii. olfactory processing iv. memory

B. Subcortical white matter I.

Internal capsule: contains fibers travelling to and from the cerebral cortex. The ascending fibers of the internal capsule are mostly originating from thalamic cells.

For example, cells in the medial geniculate nucleus of the thalamus (the nucleus that handles audition) send this auditory information to the region of cerebral cortex specialized for hearing. The descending fibers of the internal capsule are predominantly from the cerebral cortex and targeting subcortical nuclei and the spinal cord. For example, the fibers from the motor area of the frontal lobe project to the spinal cord, where they activate the neurons that innervate muscles. This corticospinal pathway allows for conscious control of movement.

Netter’s Atlas of Human st Neuroscience, 1 edition, Fig. 87.6

5

Modified from Haines Atlas 9th edition. Pp. 277; Figure 8-52. You do NOT need to know the specific tract names in parentheses. a. genu: i. the word “genu” means “knee”. Here, it refers to the bend in the internal capsule. Several other structures that we will discuss in the course use the word genu (or a derivative of genu); you must specify the structure when you list it ii. contains fibers from precentral gyrus that project down to motor nuclei of the cranial nerves (in the figure above the corticobulbar fibers are in the genu) b. anterior limb: i. anterior to the genu ii. contains fibers that interconnect the dorsomedial and anterior thalamic nuclei with the frontal lobe and the cingulate gyrus c. posterior limb:

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i. posterior to genu ii. larger than the anterior limb iii. contains motor (e.g. corticospinal) and somatosensory fibers d. sublenticular limb: i. auditory radiations (from MGB) ii. travels under the lentiform nucleus (putamen + globus pallidus) e. retrolenticular limb: i. optic radiations (from LGN) ii. travels behind the lentiform nucleus

II. Commissural fibers: fibers that connect the right and left hemispheres

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a. corpus callosum: a huge commissural pathway between the hemispheres. Forms the roof of most of the lateral ventricles (anterior horn and body). Consists of four sections (though you may encounter the rostrum of the corpus callosum in various texts, you are not responsible to identify the rostrum of the corpus callosum in the laboratory. Merely know of its existence): v. rostrum vi. genu vii. body viii. splenium b. anterior commisure: located rostral to the columns of the fornix.

Interconnects various regions of the frontal and temporal lobes. c. posterior commisure: located rostral to the superior colliculus.

Interconnects caudal parts of the diencephalon (pupillary light reflex) III. Association fibers: fibers that connect areas of cerebral cortex within the same hemisphere.

Netter’s Atlas of Human Neuroscience 1st edition, Fig. I.95 The figure above (I.95) illustrates some of the association pathways. You do not need to know the names of these pathways.

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C. Basal ganglia General structural organization: Combined, the caudate nucleus and the putamen is the striatum. Combined, the putamen and the globus pallidus is the lentiform nucleus.

The basal ganglia are known for its extensive role in movement.

I. Caudate nucleus a. head b. tail II. Putamen III. Globus pallidus a. internal b. external

Netter’s Atlas of Human Neuroscience 1st edition, Fig. I.27B

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The figure above (I.27B) illustrates the shape of the basal ganglia and its spatial relationship to the thalamus. Left-anterior; right-posterior; top-dorsal; bottom-ventral. The two dashed lines represent the horizontal levels depicted in the figure below (I. 27A). Level A is represented in the left hemisphere of figure I.27A while level B is represented in the right hemisphere of figure I.27A. Notice how the position of the head/tail of caudate nucleus is slightly changing as move from level A to level B. In the laboratory is it important to remember that like many of the “C� shaped structures, the caudate also travels mediolaterally; not just anteroposteriorly and dorsoventrally.

Netter’s Atlas of Human Neuroscience 1st edition, Fig. I.27A.

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You do NOT need to know the connectivity of the basal ganglia for this lecture. This figure (18.1) shows the relationship of various nuclei in the diencephalon and telencephalon that participate in the same function. Detailed discussion of the basal ganglia will occur in the motor lectures.

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D. Hippocampus General structural organization: “seahorse�. Located internal to the parahippocampal gyrus (temporal lobe) and forms a medial wall of the inferior horn of the lateral ventricle.

The primary function the hippocampus is associated with is declarative memory.

Netter’s Atlas of Human Neuroscience 1st edition, Fig. I.31.

In the figure above (I.31) the parietal lobe, most of the frontal lobes, most of the subcortical white matter and portions of the basal ganglia have been removed to reveal the location of the hippocampus. Notice the shape of the hippocampus. Also, notice the relationship of the hippocampus to the lateral ventricles, the thalamus and the fornix. These will be important landmarks in the laboratory to orient you in a given slab. Top-anterior; bottom-posterior.

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Fornix: Prominent white matter structure containing fibers that connect the hippocampus to the hypothalamus and septal nuclei

Netter’s Atlas of Human Neuroscience, 1st edition, Fig.I.31.

The figure above (I.31) reveals the shape of the fornix. Notice that the fornix provides direct communication from the hippocampus to the mammillary bodies. Left-anterior (slightly skewed); right-posterior (slightly skewed).

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E. Amygdala General structural organization: The amygdala is located medially within the temporal lobe, internal to the uncus and anterior to the hippocampus. The primary function of the amygdala is to process emotional characteristics.

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F. Claustrum General structural organization: The claustrum is located medially to the insula and laterally to the putamen. The primary function of the claustrum is to process conscious perception. The external capsule is identified in the figure below, it is a new term for the laboratory.

Claustrum

internal capsule

External Capsule

15

G. Blood supply of the telencephalon I. Anterior cerebral artery/branches Major targets: frontal and parietal lobes II. Middle cerebral artery/branches Major targets: all lobes and the basal ganglia/internal capsule via the lenticulostriate arteries III. Posterior cerebral artery/branches Major targets: occipital/temporal/parietal lobes

Figures A19 (B&C) show the blood supply to the cerebral cortex from the major arteries. Right-anterior; left-posterior; top-dorsal; bottom-ventral. Notice how each artery supplies at least two lobes.

16

The figure above (A19; D) illustrates the blood supply to the basal ganglia via the lenticulostriate arteries.

The figure above (A20) illustrates the great arterial circle and the branches that supply the basal ganglia and thalamus. Notice how different arteries supply different regions within these structures.

17

18

H. Views of internal structure

The figure above (A16) shows two coronal views taken at different anteroposterior locations. Notice which structures are present at both levels, which structures only exist at one of the levels and those structures that exists at both levels but are dramatically different in size and/or location. For example, in A the lateral ventricles are large and located medial to the caudate nucleus. In B this remains true but, the ventricles are smaller (so is the caudate nucleus) and the temporal/inferior horn of the lateral ventricle can now been identified.

19

In the figure above (A15) the dorsal half of the left hemisphere has been removed to show the location of the fornix, hippocampus and lateral ventricle.

20

Self test questions: 1) Memory is often associated with what lobe? a. Frontal b. Parietal c. Occipital d. Temporal 2) Which statements are true? a. The fornix connects the hippocampus and the hypothalamus. b. The fornix connects the hippocampus and the septal nuclei. c. The anterior cerebral artery is the primary blood supply to the pulvinar. d. Association fibers connect right and left hemispheres. e. The anterior limb of the internal capsule is larger than the posterior limb. f. The putamen with the globus pallidus are known as the lentiform nucleus. g. The major function of the occipital lobe is visual processing. h. The major function of the amygdala is motor processing.

3) What arteries supply blood to the lentiform nucleus? a) Branches of PCA b) Branches of ACA c) Branches of MCA d) Thalamogeniculate arteries 4) What section would mostly likely achieve two views of the caudate nucleus on each side of the brain? a) A coronal section rostral to the thalamus b) A horizontal section ventral to the thalamus c) A coronal section caudal to the thalamus d) A coronal section through the thalamus

21

ELECTRICAL ACTIVITY – PART I Alexander Galazyuk, Ph.D.

OBJECTIVES: At the end of this lecture students will be able to:

1 list the major ions which are contributing to membrane potential generation maintenance and changes 2 describe the concentration values for K+ Na+ Ca++ Cl- in the intracellular and extracellular environments 3 describe the fundamental principles behind establishing of concentration and electrical gradients for different ions across the cellular membrane and their contribution to equilibrium potential 4 describe what ion makes the more significant contribution to the resting membrane potential and why 5 the major principles underlying membrane potentials generation 6 list approximate equilibrium potentials values for K+ Na+ Ca++ Cl- and describe how to calculate it by using Nernst equation 7 describe Goldman equation and how it differs from Nernst equation 8 describe structure and basic function of active ion transporters

1 Â

ELECTRICAL SIGNALS OF NERVE CELLS External (internal as well) stimuli (visual, auditory, somatosensory, etc.) trigger electrical signals in neurons. These inputs cause electric currents to flow across the plasma

membrane of the neuron. Since the plasma membrane has a certain resistance to current flow, the flowing current causes a difference in potential (or voltage) to be developed across the membrane. The magnitude of this potential change is proportional to the magnitude of current flowing across the membrane.

Membrane potential changes are relatively small (millivolts), as in the potentials that develop across receptors in the skin (e.g. Pacinian corpuscles) and at synaptic contacts, or large, as in action potentials, which develop mainly in axons and dendrites.

These changes in electrical potentials usually last milliseconds rarely seconds.

The membrane potentials can be measured by inserting a micro-electrode through the plasma membrane into the cell. When the electrode is inserted into the cell the electrode measures the potential of the membrane at rest, or the resting membrane potential. For most neurons, the resting potential is ranging from -50 mV to -70 mV (1 mV (millivolt) = 10-3V). The potential is negative with respect to the fluid outside the cell.

2 Â

PASSIVE AND ACTIVE ELECTRICAL SIGNALS IN A NERVE CELL Instead of generating an action potential by activating a synaptic input to the neuron, an action potential can be generated by passing a small current pulse into the neuron (mimicking a synaptic input which generates a small current across the plasma membrane of the neuron).

In the laboratory, action potentials are generated and recorded by inserting two electrodes into the cell body of a neuron. One electrode – the stimulating electrode – passes small current pulses into the neuron. The second electrode – the recording electrode, measures the voltage change that occurs across the membrane as a result of the current injected. If a negative current is injected, the voltage change is negative. If a positive current is injected, the voltage change is positive. (Remember, voltage changes are positive or negative only with respect to the fluid outside the membrane, which is 0 mV). If voltage changes are small, the membrane potential does not reach threshold for generation of an action potential.

In this case, the membrane potential remains at the “subthreshold” level. This is a “passive” change. A positive voltage that takes the membrane closer to 0 mV is said to “depolarize” the membrane (less negative or closer to 0 mV). A negative voltage that takes the membrane further away from 0 mV, i.e. makes the voltage more negative, is said to “hyperpolarize” the membrane (It increases the polarization). At the resting state of the neuron, when there is no current being injected, or no inputs where arrived from other neurons, the membrane is polarized at the resting membrane potential.

Depolarization of a neuronal membrane causes excitation, whereas hyperpolarization cases inhibition.

If the positive current injected into a neuron is large enough or input from other neuron(s) is strong enough, it can cause a membrane potential (voltage) change (depolarization) that is large enough (“suprathreshold”) for generating an action potential. This is an “active” response of the membrane.

3

The creation of a resting membrane potential (1) There are differences in the concentration of ions between the two sides (inside and outside) of the membrane. Ion concentration gradients are established by proteins known as active transporters, which actively move ions into or out of cells. This movement occurs against the concentration gradient for each ion.

(2) Membranes are selectively permeable to one or more ions – i.e not all ions pass across the membrane with the same ease under the same conditions. The selective permeability of membranes is mainly due to the presence of ion channels in the membrane – these are proteins that allow only certain ions to pass across the membrane.

Ion channels that allow ions crossing the membrane are key players in generation of the membrane potential. Ions are passively moving through the opened channels. The main job of ion transporters, however, is to restore the concentration of different ions in the intracellular and extracellular environments.

Therefore they are moving ions in the opposite of ion channels direction. This process is active and requires energy (ATP).

Establishing a membrane potential Let’s consider two compartments (they represent the inside and outside of the nerve cell). One compartment contains a solution of ions (Na+ and Cl-). If we separate these compartments by an artificial membrane (to represent the nerve membrane).

Determine what ions are present in each compartment, and their concentrations, and control the ion gradients across the membrane.

4

+

NaCl Na+

Na+

Concentration gradient

Cl-

Na+

Cl-

Na+

Na+

Cl-

Na+

Cl-

Cl-

Cl-

ClNa+

Na+

Cl-

Na+

Cl-

Na+

Cl-

Na+

Cl-

Na+

ClCl-

Na+

Na+

Na+ Na+

Cl-

Cl-

Cl-

Na+

Na+

Cl-

Na+

Na+

Na+

Cl-

Na+

Na+

Cl-

Na+

Electrical gradient

-

NaCl

ClNa+

Cl-

Na+ Na+

Na+

Cl-

Na+

Cl-

Cl-

Na+

Na+

Vertical dashed line in the figure on the right represents neuronal membrane which is selectively permeable for Na+ only. As the result Na+ will be moving down the concentration gradient across the membrane whereas Cl- will not because they are too big to go through the pores in the membrane. Therefore, a concentration of positive ions is relatively higher in the left compartment while concentration of negative ions is relatively higher in the right compartment. Thus this system is generating an electric potential between two compartments (similar to the resting membrane potential in a nerve cell).

Ionic basis of the resting membrane potential

The ion that is mainly responsible for setting the resting membrane potential is K+ because at rest the vast majority of K channels (leaking channels) are opened. Other ions such as Na+, Cl- and Ca++ also contribute to the resting potential, but their impact is low (majority of these channels are closed).

5 Â

Membrane potential calculation – Nernst and Goldman equations The equilibrium potential for an ion is determined from the Nernst equation: đ??¸đ?‘Ľ

đ?‘…đ?‘‡ đ?‘‹ đ?‘œđ?‘˘đ?‘Ą ln đ?‘§đ??š đ?‘‹ đ?‘–đ?‘›

Ex = equilibrium potential for any ion X R = gas constant T = temperature Z = valence (electrical charge) of ion X, (for instance 1 for K+) F = the Faraday constant (the amount of electrical charge contained in one mole of a univalent ion) [X]out and [X]in are the concentrations of the ion X outside and inside of the membrane, respectively.

Because it is easier to do calculations using base 10 logarithms and to perform experiments at room temperature this equation is simplified to: đ??¸đ?‘Ľ

58 đ?‘‹ đ?‘œđ?‘˘đ?‘Ą log đ?‘§ đ?‘‹ đ?‘–đ?‘›

So for the example, with K+ concentrations being 10 mM inside and 1 mM outside of the membrane, the equilibrium potential for K+ is: đ??¸đ?‘˜

58 đ??ž đ?‘œđ?‘˘đ?‘Ą log đ?‘§ đ??ž đ?‘–đ?‘›

58 log

1 10

58��

If K+ were the only ion to which the membrane was permeable, the membrane potential would be the same as the equilibrium potential for K+, i.e. -58 mV. But membranes are permeable to more than one ion. In this case, the membrane potential is determined by the contribution of all those ions. This is calculated using the Goldman equation: đ?‘ƒđ?‘˜ đ??ž đ?‘œđ?‘˘đ?‘Ą đ?‘ƒđ?‘›đ?‘Ž đ?‘ đ?‘Ž đ?‘œđ?‘˘đ?‘Ą đ?‘ƒđ?‘?đ?‘™ đ??śđ?‘™ đ?‘–đ?‘› đ?‘‰đ?‘š 58 log đ?‘ƒđ?‘˜ đ??ž đ?‘–đ?‘› đ?‘ƒđ?‘›đ?‘Ž đ?‘ đ?‘Ž đ?‘–đ?‘› đ?‘ƒđ?‘?đ?‘™ đ??śđ?‘™ đ?‘œđ?‘˘đ?‘Ą P represents the permeability of the membrane to each ion. When the membrane is permeable to only one ion, the Goldman equation reduces to the Nernst equation for that ion. Note that Goldman equation includes membrane permeability (P) to a given ion. If this value is low for a particular ion, this ion would have a small contribution to the overall membrane potential.

Note that the valence factor (z) used in the Nernst equation has been removed from the Goldman equation. Therefore, the concentrations of the negatively charged chloride ions (Cl-) are inverted relative to the concentrations of the positively charged ions simply because –log (A/B) = log (B/A).

6 Â

Neuronal membranes have resistance (R) to ion current (I) flowing through the channels. This current causes a potential (E) across the membrane. The value of this potential can be calculated by Ohm’s law.

E=IR TRANSPORTERS 1. Active transporters (“active” = requiring energy = ATP) create and maintain ion gradients.

2. None of the ions that are physiologically relevant – Na, K, Ca, etc, are in electrochemical equilibrium. Because these ions diffuse down their concentration gradients, there would be a gradual dissipation of these gradients unless cells can restore ions that are displaced. This restoration, which goes against the natural concentration gradient of the ion, requires energy – hence active transport.

3. Active transporters work by forming complexes with the ions they transport. Ion binding and unbinding requires several milliseconds, hence transporters work slowly compared to ion movement through many ion channels.

4. So active transporters gradually store energy in the form of ion concentration gradients, whereas ion channels rapidly dissipate this energy during brief signaling events.

5. Some transporters are powered by ATP hydrolysis (A, B); others use electrochemical gradients as an energy source – e.g. ion exchangers (C, D) that exchange ions between the two sides of the membrane and co-transporters (EG) that carry multiple ions in the same direction.

7

I.

ATP-dependent active transport: The Na-K-ATPase pump

     

The Na/K pump accounts for 20-40% of the brain’s energy consumption.

The pump is an integral membrane protein with two subunits –  and .

It binds both Na and K. It binds ATP. It moves Na out of the cell and K into the cell.

The radioactive efflux experiments show the dependence of Na efflux on external K and intracellular ATP.  Uphill movements of Na and K are driven by ATP, which phosphorylates the pump.  The flux is asymmetrical, with 3 Na+ moved out for every 2 K+ moved in.

8

II.

ATP-dependent active transport: Calcium pumps

The Ca-ATPase pump 1. There are two different types of Ca pumps (one moves Ca outside the cell, another move Ca in Ca storage inside the cell). Uses ATP to translocate Ca from the cytoplasm across the membrane of the sarcoplasmic reticulum (which is an intracellular storage site for Ca; analogous to endoplasmic reticulum).

2. It is a large membrane protein that spans the membrane 10 times.

3. Similar to Na-K-ATPase – nucleotide binding domain that binds ATP-ADP; other domains involved in phosphorylation and ion translocation.

4. Ca first binds to cytoplasmic side of pump, and then is driven through the membrane as a result of phosphorylation-induced conformational changes in membrane-spanning domains.

9 Â

ELECTRICAL ACTIVITY – PART II Alexander Galazyuk, Ph.D.

OBJECTIVES: At the end of this lecture students will be able to:

1 explain the major principles underlying action potential formation 2 describe the contribution of voltage-gated Na and K channels to action potentials 3 describe the contribution of voltage-gated Na+ and K+ conductances in an action potential generation 4 explain the contribution of refractory periods in directional control of action potential propagation 5 explain the differences in action potential conduction between unmyelinated and myelinated nerve axons

1

THE IONIC BASIS OF ACTION POTENTIALS The creation of an action potential At rest the membrane is being permeable to K+ via leaking K channels. During action potential generation it becomes permeable to Na+ and then to K+ via voltage-gated Na and K channels. The steps to an action potential are: (1) At rest membrane mainly permeable to K+, therefore its membrane potential is negative ~ -70 mV. (2) Membrane permeability to Na increases suddenly when the membrane is depolarized to a particular level (threshold). The Na equilibrium potential is ~+55 mV (calculated by Nernst equation). So the membrane potential becomes more positive (depolarized), going towards +55 mV. (3) Then, the Na permeability decreases due to Na voltage-gated channels inactivation whereas the K permeability increases, because K voltage-gated channels are opened. Therefore the membrane potential starts to return fast back to the resting state because equilibrium potential for K+ is approximately -80 mV. (4) This sequential activation of Na and K voltage-gated channels gives rise to the action potential.

PK = permeability of the membrane to K+ PNa = permeability of the membrane to Na+

2Â Â

Membrane conductance to Na and K currents During an action potential the Na current has a rapid rise time of a fraction of a millisecond, and decay back to baseline within 1-1.5 ms. When the voltage-gated channels are opened both concentration and electrical gradients forced Na+ inside the neuron (see Electrical Activity – Part I lecture for further details). Therefore Na+ conductance is very high. The K current rises very slowly, because concentration gradient moves K+ out, whereas electrical gradient forces them moving inside the neuron.

By the time the K current starts to rise, the Na current has almost completely decayed to baseline. Thus the Na and K currents activate in sequence during an action potential. The K conductance helps faster to repolarize the membrane potential and terminate the action potential.

Tetrodotoxin, a puffer fish poison, is known to block voltage-gated Na channels.

Tetrodotoxin inhibits the firing of action potentials in nervous system by binding to the voltage-gated sodium channels causing immediate death.

Lidocaine, a blocker of voltage-gated Na channels is the most commonly used local anesthetic. It enters neurons or neuronal axons through the Na channels when they are opened and binds to these channels from the inside.

3Â Â

REFRACTORY PERIOD

Following an action potential, the axon experiences a brief refractory period, during which it is resistant to further excitation. This refractory period lasts for several milliseconds following the initial action potential. The refractory period is divided into two components; the first 2-4 ms is the absolute refractory period, during which an action potential cannot be generated. The next several milliseconds, between 4-10 ms, is the relative refractory period, during which an action potential can be generated, but requires stronger input (stimulus).

During the relative refractory period, the action potential does not attain its full height. The refractory period is caused by inactivation of Na channels following an action potential. Na channel inactivation is dependent on both voltage and time. The high depolarizing voltage at the peak of the action potential inactivates Na channels, and they take time (the refractory period) to recover from their inactivation.

CONDUCTION OF AN ACTION POTENTIAL DOWN AN AXON There are two major types of axons in the nervous system: unmyelinated and myelinated.

These is a fundamental difference in action potential propagation between these two axon types.

There are two main ways to increase action potential conduction velocity: (1) Increasing the axon diameter decreases resistance to passive current flow down the axon. Therefore in the larger axon the same passive current can trigger an action potential in more distal adjacent segments of the axon. Large diameter axons conduct faster than small diameter axons.

(2) Insulating the axon membrane prevents the leak or loss of passive current out of the axon. This is done by myelinating the axon. Myelination is a process by which glial cells (oligodendrocytes in the CNS, Schwann cells in the peripheral nervous system) wrap the axon in myelin – multiple layers of glial membranes. This insulation makes the membrane less leaky and current flows through the cytoplasm down the axon instead of out of the membrane.

4

Action potential propagation in unmyelinated axons Depolarization opens voltage-gated Na and K channels locally and produces an action potential at point A of the axon (time t=1). The resulting current flows passively down the axon, depolarizing the adjacent region (point B). At a later time (t=2), the depolarization of the adjacent membrane has opened Na and then K channels at point B, resulting in the initiation of the action potential at this site and additional current that again spreads passively to an adjacent point (point C) farther down the axon. As the result, the action potential has propagated further (t=3). This cycle continues repeating along the full length of the axon. As the action potential propagates, the membrane potential behind remains at the refractory state for several milliseconds which prevents backward propagation of the action potentials.

Unlike passive currents that decrease its amplitude with distance, the action potential amplitude does not change. This is because, an action potential is constantly recreated at axon membrane when it travels down the axon. Therefore it always has the same amplitude.

The refractory period prevents backward movement of the action potential, ensuring that it moves only in one direction, down the axon towards the terminal.

5Â Â

Action potential propagation in myelinated axons In contrast to unmyelinated axons, in a myelinated axon voltage-gated Na and K channels are not evenly distributed in the axonal membrane. Instead, they localized at nodes of Ranvier (unmyelinated parts of the myelinated axon). Upon an action potential generation in the Point A (t=1) the passive current flows down the axon. This current cannot trigger an action potential in a myelinated part of the axon due to two reasons. First, the myelin prevents this current from leaking across the membrane due to the presence of myelin which works similar as insulation on electric wires. Second, in a myelinated axon voltagegated Na and K channels are present only at the nodes of Ranvier but not in the membrane under myelin. This arrangement means that the generation of active voltagegated Na and K conductances occurs only in unmyelinated nodes. As a result, the action potential jumps from node to node – referred to as saltatory conduction. As the result the action potential propagation in a myelinated axon is much faster than in an unmyelinated one (see figure on the next page for comparison).

6Â Â

Comparison of the speed of action potential conduction in unmyelinated and myelinated axons of the same diameter.

7

Clinical correlations: MULTIPLE SCLEROSIS (MS) (1) Arises from multiple regions of de-myelination and inflammation along axonal pathways.

(2) Commonly begins between ages 20-40.

(3) Characterized by abrupt onset of neurological deficits that persist for days and weeks and then subside.

(4) Ranges from no persistent neurological loss, to occasional occurrences, to progressive deterioration.

Signs and symptoms of MS are determined by the location of the affected regions.

Lesions of optic nerve – monocular blindness.

Lesions of corticospinal tract – motor weakness or paralysis Lesions of somatic sensory pathways – abnormal somatic sensations Lesions of medial longitudinal fasciculus – double vision Lesions of vestibular pathways – dizziness.

The loss of the myelin sheath around axons greatly slows action potential conduction velocity and causes abnormal patterns of nerve conduction that cause most of the clinical deficits observed. However abnormalities can occur beyond just the loss of myelin. Some axons are destroyed, probably because of inflammation that targets the remaining myelin, or loss of trophic support from the glial cells.

LIMBIC ENCEPHALITIS Limbic encephalitis is a disease characterized by an autoimmune reaction to inflammation or tumor. Typically the antibodies against anti-N-methyl-D-aspartate receptors (NMDAR) and the voltage-gated potassium channel-complex (VGKC-complex) are prodused. Reduction in the number of these channels often leads to the development of short-term memory deficits, headache, sleep disturbance, hallucinations, seizures and psychosis.

Self-test question: How do voltage-gated K channels blockers affect action potential? They will: a. b. c. d. e.

completely block action potential generation decrease the speed of the falling time decrease speed of the rising time increase speed of the falling time decrease speed of both rising and falling time

8

Yong Lu, Ph.D., Synaptic transmission I, MN

Synaptic Transmission I Learning Objectives 1. Describe the function of synaptic transmission 2. Describe the importance of action potentials as the universal signals 3. Describe the structure of electrical and chemical synapses 4. Compare electrical transmission with chemical transmission 5. List the major steps in chemical transmission 6. Describe the role of Ca2+ in chemical transmission 7. Define the functions of the highlighted proteins involved in synaptic vesicle fusion 8. Describe the life cycle of glutamate and GABA 9. Describe chemical transmission at neuromuscular junction 10. Describe the life cycle of synaptic vesicles 11. Define the following terms: synapse electrical synapse connexin transmitter vesicle transmitter receptor voltage-gated Ca2+ channel neuromuscular junction acetylcholine receptor

synaptic transmission connexon chemical synapse active zone synaptic delay gating of ion channels acetylcholine acetylcholinesterase

Reading assignment: Purves Chapters 5-7 (for lectures of Synaptic Transmission I, II, & III, and Synaptic Integration).

Answer to the practical question at the end of this lecture note: E

1

Yong Lu, Ph.D., Synaptic transmission I, MN

I. Introduction A. Knee-jerk reflex pathway 1. Muscle spindle (a sense organ) is stimulated.

2. Sensory neurons transfer information (action potentials) to motor neurons in the spinal cord that control the extensor, and to interneurons that project to the motor neurons that control the flexor muscle.

3. Motor neurons transfer information at neuromuscular junctions to muscle cells; extensor is excited and flexor is inhibited.

Synapse: the region of contact where a neuron transfers information to another cell (communicating cell-cell junction).

Synaptic Transmission: a process through which a cell transfers information to another cell through a synapse. Each cell receives numerous synaptic inputs from other neurons.

B. Where are synapses?

1. axodendritic 2. axosomatic 3. axoaxonic 4. dendrodendritic

2

Yong Lu, Ph.D., Synaptic transmission I, MN

II. Structure of synapses: electrical vs. chemical A. Electrical synapses 1. Gap junction channels connect communicating cells.

2. Large pores, non-selective, gated by multiple factors (potential, molecules, pH, etc.)

3. Electrical transmission is fast, with virtually no delay, and non-selective.

4. Electrical transmission synchronizes firing of a population of cells.

5. Electrical transmission is usually bidirectional.

Gap junctions between neurons are particularly common during early embryonic stages. During brain development, gap junctions allow neighboring cells to share both electrical and chemical signals (ions, nutrients, and small molecules with molecular weight <1000 Dalton) that may help coordinate their growth and maturation.

Each gap junction channel has 2 hemichannels. Each hemichannel, called a connexon, consists of 6 protein subunits called connexins.

Clinical note: Mutation in connexins is the most common cause for genetic deafness.

In adults, gap junctions interconnect many nonneural cells, such as glia, epithelial cells, smooth and cardiac muscle cells.

3

Yong Lu, Ph.D., Synaptic transmission I, MN

B. Chemical synapses 1. A chemical synapse has two basic elements: presynaptic terminal, postsynaptic cell membrane 1). Presynaptic cell makes the chemicals (transmitters).

2). Presynaptic terminals store, release, and recycle transmitters.

3). Synaptic vesicles contain highly concentrated transmitters.

4). Active zones: presynaptic site of transmitter release 5). Voltage-gated Ca2+ channels are clustered at active zones 6). Synaptic cleft: 20-50 nm 7). Postsynaptic membrane: transmitter receptors 2. Chemical transmission has a delay of about 0.5 ms.

3. Chemical transmission amplifies signals.

4. Chemical transmission is generally unidirectional.

5. Chemical synapses are plastic (subject to modulation, i.e., synaptic responses can be changed up and down).

Preterminal

extracellular

intracellular

extracellular extracellular

extracellular synaptic cleft (20-50 nm)

intracellular postsynaptic cell (dendrite, soma, axon)

Illustrated by Yong Lu, Ph.D. 4

Yong Lu, Ph.D., Synaptic transmission I, MN

III. Major steps in chemical transmission (commonly referred as electro-chemical transmission, synaptic transmission, or neurotransmission): A. Action potential at the presynaptic terminal initiates the whole process 1. Action potentials are ELECTICAL signals generated by excitable cells.

2. Action potentials can be generated spontaneously, e.g. by pacemakers in CNS or in the heart.

3. Action potentials result from receptor potentials generated by sensory receptors in response to sensory stimuli.

4. Action potentials depolarize the membrane of the presynaptic terminal.

- + + - + + - + + - + + - + ++ + + + + + + + - - - - - - - - - -

0 mV

Illustrated by Yong Lu, Ph.D.

B. Voltage-gated Ca2+ channels are activated (opened), and Ca2+ ions enter the presynaptic terminal 1. Electrical force is against influx of Ca2+ ions 2. However, chemical force is for influx of Ca2+ ions 3. The net, electrochemical gradient (force) favors influx of Ca2+ ions

5

Yong Lu, Ph.D., Synaptic transmission I, MN

C. Ca2+ entry causes vesicle fusion with cell membrane and transmitter release 1. Synaptic delay arises mainly from this step 2. Four Ca2+ ions are needed for each vesicle release 3. Many proteins are involved Synaptotagmin: Ca2+ binding (sensor) Synaptobrevin: SNARE component Transmitter transporters: accumulation of transmitter molecules in synaptic vesicles Proton pump: provide energy for transmitter transporters Other proteins: trafficking and targeting, and unknown functions

Synaptotagmin

Synaptobrevin

Proton pump

Transmitter transporters

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 8.4

6

Yong Lu, Ph.D., Synaptic transmission I, MN

SNARE complex = Synaptobrevin + Syntaxin + SNAP-25

D. Transmitters diffuse across the synaptic cleft 1. Most transmitter molecules donâ&#x20AC;&#x2122;t make to the postsynaptic membrane 2. Some diffuse to non-synaptic space (spillover) E. Transmitter molecules bind to postsynaptic receptors 1. Some postsynaptic receptors are ion channels (pore proteins). These ion channels can be directly gated (open only) by transmitters.

2. Other postsynaptic receptors are metabotropic receptors, and they can indirectly gate (open or close) ion channels. ions (Na+, K+, Ca2+, Cl-)

G-pro

A cascade of events

Illustrated by Yong Lu, Ph.D. 7

Yong Lu, Ph.D., Synaptic transmission I, MN

F. Ions flow across the membrane of the postsynaptic cell 1. Which ion(s) to flow depends on receptor type.

2. Which direction the ions flow depends on their electrochemical gradient.

3. The net flow of ions determines depolarization or hyperpolarization.

G. Postsynaptic cell is either depolarized or hyperpolarized 1. A net flow of positively charged ions into the cell leads to membrane depolarization (EPSP: excitatory postsynaptic potential).

2. A net flow of negatively charged ions into the cell leads to hyperpolarization (IPSP: inhibitory postsynaptic potential).

3. A net flow of positively charged ions out of the cell leads to hyperpolarization.

4. A net flow of negatively charged ions out of the cell leads to depolarization.

H. Termination of synaptic transmission 1. Diffusion of transmitter molecules 2. Inactivation by enzymes: primarily at cholinergic synapses 3. Re-uptake by preterminals and glial cells: most common mechanism for non-cholinergic transmission

transmitter vesicle

preterminal

transmitter molecule

glial cell

transmitter receptors active zone 2nd messenger Ca2+ channel

ions

postsynaptic cell

excitation or inhibition

EPSP

IPSP

Illustrated by Yong Lu, Ph.D.

8

Yong Lu, Ph.D., Synaptic transmission I, MN

Life cycle of neurotransmitters: Glutamate: most abundant excitatory transmitter; transported into synaptic vesicles by VGluT (vesicular glutamate transporter), after release, uptaken by glial cells via EAAT (excitatory amino acid transporter), converted to Glutamine (Gln) by glutamine synthetase (glutamate synthase), Gln diffuse out glia (or transported by system N 1 transporter, or reverse transport by EAAT) and enter glutamatergic presynaptic terminal (diffusion or by system A transporter 2), converted to Glu by glutaminase. Some Glu are uptaken by presynaptic terminal via EAAT. GABA (g-Aminobutyric Acid): most abundant inhibitory transmitter; transported into synaptic vesicles by VIAAT (vesicular inhibitory amino acid transporter), after release, uptaken into presynaptic terminal via GAT (GABA transporter), broken down by GABA-T (GABA transaminase), converted to Glu, converted to GABA by GAD (glutamic acid decarboxylase). Some GABA are uptaken by glia cells, converted to glutamine, diffuse into presynaptic terminal, converted to Glu, then GABA.

9

Yong Lu, Ph.D., Synaptic transmission I, MN

IV. Chemical transmission at neuromuscular junction (NMJ) A. Structure of NMJ: note the location for three different types of ion channels (VGCC, nAChR, Nav)

B. Steps of chemical transmission at neuromuscular junction (NMJ): 1. AP is generated by a motor neuron and arrives the nerve terminal.

2. AP depolarizes the nerve terminal; Ca2+ channels are activated, allowing Ca2+ enter the nerve terminal.

3. Acetylcholine (ACh) molecules in synaptic vesicles are released.

4. ACh molecules diffuse through the space between the neuron and the muscle.

5. ACh molecules bind to ACh receptors on the muscle membrane.

6. Ions flow through the receptors (Na+ in and K+ out, a net influx of positivelycharged ions).

7. Muscle cell is depolarized (end-plate potential, EPP).

8. Transmission is terminated primarily by acetylcholinesterase (AChE).

10

Yong Lu, Ph.D., Synaptic transmission I, MN

Clinical note: disorders that affect the presynaptic terminal In Lambert-Eaton myasthenic syndrome patients (associated with certain cancers), antibodies against VGCCs are produced (autoimmune), causing muscle weakness.

Botulinum toxins destroy SNARE protein and thus neurotransmission, esp. at NMJ causing paralysis. Tetanus toxin destroys synaptobrevin in inhibitory neurons in the CNS causing dis-inhibition and over-excitation of motor neurons.

Life cycle of synaptic vesicles Transmitter-filled vesicles form a vesicle cluster (pool), fuse with presynaptic terminal membrane to release content, clathrin-mediated endocytosis produce new vesicles, which either fuse with endosome and form new vesicles by budding, or directly become vesicles to be filled. Kiss and run: no fusion of the vesicles during release.

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 8.2

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Yong Lu, Ph.D., Synaptic transmission I, MN

Sample question Which statement is true?

A. Electrical transmission is an electrochemical process during which presynaptic activity is transferred to the postsynaptic cell through transmitters.

B. Chemical transmission has virtually no delay because transmitter molecules released from synaptic vesicles can diffuse extremely fast.

C. Action potential of the postsynaptic cell initiates the process of chemical transmission through synapses impinging onto the postsynaptic cell.

D. One neuron can have either chemical or electrical synapses on its membrane, but not both.

E. At chemical synapses, the space between the pre- and postsynaptic membrane is larger than the space found between two paired connexons at electrical synapses.

Answer: see the first page of this lecture note

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Yong Lu, Ph.D., Synaptic transmission II, MN

Synaptic Transmission II Learning Objectives 1. Describe the criteria for a chemical to be a neurotransmitter, and be able to give an example 2. Be familiar with synthesis, storage and release of major neurotransmitters 3. Compare ionotropic and metabotropic receptors 4. Describe the ion basis for EPSP and IPSP 5. List the names of ionotropic and metabotropic receptors activated by different transmitters (see summary in the Table at the end of the lecture note) 6. Describe the basic structure (at the subunit level) and function of major ionotropic receptors (AChR, iGluR, GABAAR, glycine receptors) 7. Define the following terms: neurotransmitter ionotropic receptor EPSP nicotinic receptor NMDA receptor AMPA receptor GABAA receptor glycine receptor antagonist

ligand metabotropic receptor IPSP muscarinic receptor non-NMDA receptor kainate receptor GABAB receptor agonist

Answer to the practical question at the end of this lecture note: D

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Yong Lu, Ph.D., Synaptic transmission II, MN

I. Neurotransmitters (review the lecture on this topic given in Molecules to Cells) A. Criteria for a chemical to be considered as a neurotransmitter. A neurotransmitter 1. is synthesized in the presynaptic neuron (terminals and/or cell body).

2. is released at the presynaptic terminal, binds to postsynaptic receptor, and gives rise to a postsynaptic effect.

3. when applied exogenously, mimics the effect by endogenous release.

4. is inactivated by specific mechanisms.

B. Major neurotransmitters Small-molecule transmitters include acetylcholine, 3 amino acids (glutamate, GABA, glycine), 5 biogenic amines (dopamine, norepinephrine, epinephrine, serotonin, histamine). More than 50 neuroactive peptides can be used as transmitters as well. Neuroactive peptides as transmitters compared to smallmolecule ones 1). Made in cell body only 2). Stored in large dense-core vesicles 3). Released in response to general intracellular Ca2+ increase 4). No re-uptake 5). Longer action Others: ATP, nitric oxide, etc.

II. Receptors A. Criteria for receptors? Not as strict as for transmitters. A receptor 1. is synthesized by neurons in the cell body or dendrites 2. must be inserted into the cell membrane to be functional 3. is able to bind with transmitter molecules, change configuration, and give rise to an effect on the cell

Illustrated by Yong Lu, Ph.D.

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Yong Lu, Ph.D., Synaptic transmission II, MN

B. Ionotropic vs. metabotropic receptors 1. Ionotropic receptors 1). are ion channels (pore proteins) 2). consist of multiple subunits (3-5 subunits) 3). are directly gated by ligands (transmitters), allowing ions to flow 4). mediate fast actions 2. Metabotropic receptors 1). are membrane proteins, but not ion channels 2). have seven transmembrane domains (TMD) 3). are usually G-protein-coupled receptors (GPCR) 4). mediate relatively slow actions

G-protein

Illustrated by Yong Lu, Ph.D. C. Excitatory vs. inhibitory synapses: connection 1. Synaptic inputs on dendrites (axodendritic) are often (not always) excitatory.

2. Synaptic inputs on cell bodies (axosomatic) are often inhibitory.

3. Synaptic inputs on axon terminals (axoaxonal) are often modulatory.

4. Dendrodendritic inputs can be either excitatory, inhibitory, or modulatory

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Yong Lu, Ph.D., Synaptic transmission II, MN

D. Excitatory vs. inhibitory synapses: morphology Excitatory and inhibitory synapses have distinctive structures.

1. Excitatory synapses have asymmetrical membrane differentiations, and transmitter vesicles are often round in shape.

2. Inhibitory synapses have symmetrical membrane differentiations, and transmitter vesicles are often flat or oval in shape.

3. Note: one cell can receive many excitatory and inhibitory inputs.

Note: these morphological criteria are indicative (but not the golden standards) of excitatory or inhibitory synapses.

E. Excitatory vs. inhibitory synapses: physiology (EPSP and IPSP) 1. Postsynaptic potentials (PSPs) can be recorded experimentally.

2. EPSP results from a net flow of positively charged ions (Na+, Ca2+, and/or K+) entering the cell at the resting membrane potential (RMP).

3. IPSP results from a net flow of negatively charged ions (e.g., Cl-) entering the cell at the RMP.

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Yong Lu, Ph.D., Synaptic transmission II, MN

Illustrated by Yong Lu, Ph.D. +

Na Vm

EPSP

-65 mV

Time

-----------------------------------------------------------------------------------------------------------

Illustrated by Yong Lu, Ph.D.

-

Cl Vm

-65 mV IPSP Time

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Yong Lu, Ph.D., Synaptic transmission II, MN

F. Major receptors 1. Acetylcholine receptors (AChR) 1). Ionotropic ACh receptor (nicotinic receptor): most common/typical nicotinic receptors have 5 subunits (pentamer); 2 ACh molecules bind with 2 subunits (the binding sites are located between one alpha subunit and a non-alpha subunit), activated receptors allow Na+ and K+ to flow (Na+ in and K+ out, at resting membrane potential) across membrane, generating depolarization.

2). Metabotropic ACh receptors: muscarinic receptors, G-proteincoupled receptor (GPCR); in some cells decrease a slowly activating, voltage-gated K+ current, help set RMP and control excitability; in other cells, modulatory actions.

Note terms: transmitter, agonist, antagonist, and ligand

ACh Nicotine

Muscarine

Curare

Atropine

Nicotinic receptor

Muscarinic receptor

Illustrated by Yong Lu,

Neuroscience, Fig. 6.3

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Yong Lu, Ph.D., Synaptic transmission II, MN

Different subunits of nAChRs depending on location of the receptors.

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 9.10

Why nAChRs are permeable to cations, but not anions? There are 3 “rings” formed by amino acids from the subunits, and most of the amino acids are the 2 amino acids that are negatively charged (Glu: glutamate; Asp: aspatate). The negative charges attract cations and repel anions.

Why nAChRs allow both Na+ and K+ ions to flow (unlike voltage-gated Na+ or K+ channels, which are selective for just one type of ions)?

Larger pore size—this is true for lots of ionotropic receptors.

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 9.5

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Yong Lu, Ph.D., Synaptic transmission II, MN

2. Glutamate receptors (GluR) 1). Ionotropic glutamate receptor (iGluR): AMPAR, NMDAR, Kainate receptors; each receptor has 4 subunits (tetramer), and each subunit has 3 TMDs. Two glutamate molecules bind and activate each receptor.

Glutamate

AMPA

Kainate

NMDA

AMPA receptor

NMDA receptor

Kainate receptor

Illustrated by Yong Lu, Ph.D. a. AMPARs mediate fast excitatory transmission, permeable to Na+ and K+ (some also permeable to Ca2+). b. NMDARs mediate relatively slow excitatory transmission (compared to AMPARs), are highly permeable to Ca2+, need glycine as cofactor, are blocked by Mg2+ at RMP, have binding sites for Zinc (Zn2+ blocks NMDARs in a non-competitive and a voltage-independent manner) and PCP (phencyclidine; angel dust, which blocks NMDARs, causing euphoria followed by loss of balance, sweating, seizures, and respiratory depression), and are important in synaptic plasticity and glutamate excitotoxicity. c. Kainate receptors are similar to AMPARs, but not well understood.

2). Metabotropic glutamate receptor (mGluR): are GPCRs, mGluR 18 (3 groups); modulation of neuronal properties.

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Yong Lu, Ph.D., Synaptic transmission II, MN

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 11.7

Purves et al., Neuroscience, Fig 6.8

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Yong Lu, Ph.D., Synaptic transmission II, MN

Squire et al., Fundamental Neuroscience, 2nd ed, Fig 11.7

3. GABA receptors 1). Ionotropic GABA receptor: GABAaR (well understood), GABAcR (not well understood); similar to AChR in structure, one receptor has 5 subunits, each subunit has 4 TMDs. 2 GABA molecules bind to 2 alpha subunits, allows Cl- to flow into the cell (in most mature neurons), producing hyperpolarization (IPSP), have many drug binding sites (benzodiazepine and barbiturates potentiate GABAaR response) 2). Metabotropic GABA receptor: GABAbRs are GPCRs, mediating modulation of ion channels and synaptic transmission

GABA muscimol

baclofen

gabazine

phaclofen

GABAaR

GABAbR Illustrated by Yong Lu, Ph.D. 10

Yong Lu, Ph.D., Synaptic transmission II, MN

4. Glycine receptors 1). Ionotropic glycine receptors: similar to AChR, has 5 subunits; 3 glycine molecules bind to 3 a subunits, Cl- flow into the cell; blocked by strychnine.

2). Metabotropic glycine receptors: none

Food for thought Both GABA and glycine cause inhibition, via generating IPSPs. The differences reside in the locations where these two neurotransmitters are released. In the spinal cord and lower brainstem, glycine is the dominant inhibitory transmitter. In higher brain structures, GABA is the dominant one. In contrast, glutamate is the most dominant excitatory transmitter throughout the CNS.

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Yong Lu, Ph.D., Synaptic transmission II, MN

5. Other ionotropic receptors: purinergic receptors, serotonin receptors Transmitter ACh Glutamate GABA Glycine ATP Serotonin (5-HT) Catecholamines (NE, Epinephrine) (Dopamine) Histamine Light Odorants Peptides

Ionotropic receptor Nicotinic receptor iGluRs GABAaR, GABAcR Glycine receptor P2X receptor 5-HT3 receptor ---------------------------

Metabotropic receptor Muscarinic receptor mGluRs GABAbR -----P2Y receptor 5-HT1,2,4-7 receptors a1, a2, b D1-5 receptors H1-5 receptors Rhodopsin >500 odorant receptors Opiod receptors, etc.

1). 5-HT3 (5hydroxytryptamine) receptors are ionotropic receptors, similar to nicotinic ACh receptors in structure; nonselective cation channel; when activated, resulting in EPSP.

2). Each P2X receptor has 3 subunits (trimer), and each subunit has 2 transmembrane segments.

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Yong Lu, Ph.D., Synaptic transmission II, MN

Summary:

In the â&#x20AC;&#x153;knee-jerk responseâ&#x20AC;? circuit, one can record action potential (AP) from the sensory neuron (cell body in dorsal root ganglion), EPSP (in response to glutamate) and AP in the motor neuron in spinal cord that innervates the extensor muscle, EPSP (in response to glutamate) and AP in the interneuron in spinal cord that innervates another motor neuron, IPSP (in response to glycine and/or GABA) in the motor neuron in spinal cord that innervates the flexor muscle, EPP and AP in extensor muscle, and no response in flexor muscle.

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Yong Lu, Ph.D., Synaptic transmission II, MN

Sample question (Answer: see the first page of this lecture note) Which one of the following neurotransmitters binds and activates ionotropic but not metabotropic receptors on the postsynaptic membrane?

A. serotonin B. GABA C. glutamate D. glycine E. ATP

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Yong Lu, Ph.D., Synaptic transmission III, MN

Synaptic Transmission III Learning Objectives 1. Explain why the time course of metabotropic receptor-mediated responses is slower than that of ionotropic receptor-mediated responses 2. Describe the operation of G-proteins, and the common features for G-proteincoupled signaling pathways 3. Compare the membrane-delimited pathway and second messenger-mediated pathways for GPCRs 4. Describe in detail the cascade of cellular events involved in one of the second messenger pathways: cAMP pathway 5. Be familiar with other second messenger pathways 6. Describe the importance of GPCR-mediated signaling pathways 7. Describe how GPCR-mediated effects are terminated at different stages along transduction pathways 8. Describe the actions of tetrodotoxin and botulinum toxin on synaptic transmission 9. List the synaptic abnormalities underlying dysfunctions of the NMJ in myasthenia gravis (MG) 10. Explain the mechanisms for drug treatment of MG by AChE inhibitors Answer to the practical question at the end of this lecture note: D

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Yong Lu, Ph.D., Synaptic transmission III, MN

I. Synaptic transmission mediated by metabotropic receptors: slow synaptic action A. Example: muscarinic ACh receptors mediate a slow EPSP (autonomic ganglia) 1. Nicotinic ACh receptors mediate a fast EPSP; ACh directly gates ionotropic ACh receptors, allowing a net flow of positively charged ions into the postsynaptic cell and giving rise to fast depolarization (ms in time).

2.

A slow EPSP is mediated by muscarinic ACh receptors; ACh indirectly gates a type of K channels (M-type) via a cascade of cellular events.

Activated muscarinic ACh receptors eventually lead to closure of the K channels (these channels are open at rest), resulting in a decrease in efflux of positively charged K ions and giving rise to depolarization (e.g. in neurons of the autonomic ganglia). It takes longer time for the effects to occur, and it also takes longer time for the effects to disappear (seconds to minutes; note the time scale in figure B), compared to the effects mediated by ionotropic receptors.

3.

The indirect gating of M-type K channels by ACh affects neuronal firing properties. E.g., under control conditions, a neuron may fire just one action potential (spike) in response to a prolonged current injection into the cell, due to the presence of M-type K channels (and thus inhibition of firing). When muscarinic receptors are activated, the excitability of the cell is increased because of the closure of M-type K channels. The cell can fire multiple spikes to the same stimulus.

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Yong Lu, Ph.D., Synaptic transmission III, MN

B. GPCRs and operation of G-proteins 1. A GPCR (G-protein-coupled receptor) consists of a single polypeptide containing 7 membrane-spanning alpha helices (or 7 TMDs, transmembrane domains). Also called heptahelical receptor.

Examples: b2-adrenergic receptor, rhodopsin, cannabinoid receptor.

2. G-protein: guanosine triphosphate (GTP)-binding protein. Each Gprotein has 3 subunits, a, b, and g. There are about 20 types of Gproteins. Note that because there are ~1,000 types of GPCRs, some G-proteins can be activated by many different receptors.

3. All G-proteins have the basic common mode of operation 1). At the resting (inactive) state, a guanosine diphosphate (GDP) molecule is bound to the Ga. 2). When the receptor is activated (transmitter molecules bind the receptor), the GDP is released, and replaced by a GTP. 3). The activated G-protein splits to form two active components: Ga subunit and Gbg complex. Both can stimulate various effector proteins (We will study the signaling pathways below).

4). The Ga subunit is itself a GTPase, which can break down GTP into GDP and a phosphate group (PO4) (GAP, GTPaseactivating protein facilitates the process), terminating Ga activity. Ga and Gbg then come back together and bound with a GDP again to form an inactive G protein.

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Yong Lu, Ph.D., Synaptic transmission III, MN

C. G-protein-coupled signaling transduction pathways 1. The shortcut pathway (membrane-delimited pathway) vs. second messenger cascades.

1). The shortcut pathway: activated Gbg complex directly gates (opens or closes) ion channels. Faster than second messenger cascades, but slower than ligand-gated ion channels.

Examples: in the heart, muscarinic ACh receptors (activated by ACh released from the vagus nerve) act in this way. Activated Gbg complex opens nearby K channels (G-protein-regulated inward rectifier), K ions flux out, hyperpolarizing heart muscle cells and slowing down heart rate. Note that the Gbg complex here opens the K channels. In other places (e.g., presynaptic terminals of many neurons), Gbg complex can inhibit voltagegated Ca channels, reducing transmitter release (weâ&#x20AC;&#x2122;ll learn more about this in the next lecture, Synaptic Integration).

2). Second messenger cascades: G-proteins activate enzymes that trigger a series of biochemical reactions inside the cell. This cascade of intracellular events leads to the activation of other enzymes that change many cellular functions. Molecules between the first enzyme and the last are termed second messenger(s). Note that the transmitter molecules released at the synapses are the first or primary messengers. In the example shown here, the effects of the second messenger system are inhibition of Na as well as Ca channels and thus inhibition of heart muscle contraction.

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Yong Lu, Ph.D., Synaptic transmission III, MN

2. Classical cAMP (cyclic adenosine monophosphate) pathway 1). Neurotransmitter norepinephrine (NE) binds to b-adrenergic receptor (e.g. in heart cells), one type of metabotropic receptors for NE. 2). The b- adrenergic receptor changes its configuration and activates Gs, with GDP being exchanged for GTP. The Gprotein is called Gs because it stimulates/activates an enzyme adenylyl cyclase. If NE binds to another type of receptors (a2 receptors, e.g. on presynaptic terminals), it will activate a different type of G-protein, and inhibits adenylyl cyclase; hence the G-protein is named Gi. Therefore, the same neurotransmitter molecule can give rise to totally different effects by binding to different receptors (more examples below).

3). The activated G-protein splits into two parts, the Ga subunit and the Gbg complex. Ga subunit activates (if itâ&#x20AC;&#x2122;s a Gs) (or inhibits if itâ&#x20AC;&#x2122;s a Gi) the enzyme adenylyl cyclase (AC).

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Yong Lu, Ph.D., Synaptic transmission III, MN

4). AC converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP); this can be repeated many times (AC is an enzyme) (amplification of signals). cAMP diffuses in the cytoplasm, serving as a second messenger to activate another enzyme protein kinase A (PKA). Each PKA has 2 regulatory and 2 catalytic subunits. On each regulatory subunit, there are 2 binding sites for cAMP. At rest state (no cAMP present), the catalytic domains are inactive. After four cAMP molecules bind to the 2 regulatory subunits, the catalytic subunits are liberated and activated. Note that cAMP can be converted to AMP (inactivated) by Phosphodiesterases (one of many ways to terminate the signaling pathway).

5). The catalytic subunits of PKA can phosphorylate target proteins (adding a phosphate group onto the target protein, at the same time transferring ATP to ADP), giving rise to cellular responses (e.g. NE increases heart rate by binding to adrenergic b receptors and leading to increase in calcium channel activity). Dephospharylation: protein phosphatases inactivate phosphorylated protein (active form) by removing phosphate groups and releasing inorganic phosphate Pi.

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Yong Lu, Ph.D., Synaptic transmission III, MN

3. G-protein-coupled signaling pathways follow a common plan.

4. Phosphoinositol system (PLC pathway): e.g., activation of group I mGluRs results in activation of another kind of G-protein (Gq), which activates an enzyme phospholipase C (PLC); PLC breaks down phosphatidylinositol biphosphate (PIP2) into diacylglycerol (DAG) and inositol triphosphate (IP3), two second messengers; DAG activates protein kinase C, IP3 binds with IP3 receptors (ion channels) on ER membrane, causing release of Ca2+ from ER; PKC can lead to protein phosphorylation, and Ca2+ can act as another second messenger, giving rise to a variety of cellular responses.

Group I

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Yong Lu, Ph.D., Synaptic transmission III, MN

Note: again, different receptors lead to totally different effects through different signaling pathways. While group I mGluRs use the PLC pathway for signaling transduction, groups II and III mGluRs are linked to Gi protein and down-regulation of PKA activity. Similarly, D1 receptors for dopamine leads to activation of PKA, whereas D2 receptors inhibition of PKA.

5. Function of GPCR signal cascades: signal amplification.

This can occur at several stages.

A single transmitter molecule, bound to one receptor, can activate 1020 G-proteins; each G-protein can activate an adenylyl cyclase, which can make many cAMP molecules. Many PKA can be then activated and each PKA can phosphorylate many channel proteins. Therefore, signal transduction pathways via second messenger systems can amplify signals & produce larger and longer-lasting effects than ionotropic receptor-mediated responses.

6. Termination of GPCR effects 1) 2) 3) 4) 5)

cease of stimulus and release of transmitters diffusion, degradation, uptake of transmitters desensitization of receptors GTPases break down GTP Phosphodiesterases convert cAMP to AMP 6) Protein phosphatases cause dephosphorylation of phosphorylated proteins

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Yong Lu, Ph.D., Synaptic transmission III, MN

Summary: GPCRs

Ca2+ regulation: Ca2+ is a very important signaling molecule in neurons. It triggers transmitter release, regulates ion channel activity, and functions as a second messenger. Homeostasis of intracellular free Ca2+ concentration is critical for cell functions and survival. Pathways leading to increase of intracellular Ca2+ include activation of VGCCs, ligand-gated channels (AMPAR, NMDAR, nAChR), IP3Rs, and ryanodine receptors. Pathways leading to decrease of intracellular Ca2+ include activation of Na+/Ca2+ exchangers, Ca2+ pumps, and Ca2+ binding buffer proteins.

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Yong Lu, Ph.D., Synaptic transmission III, MN

II. Synaptic transmission, ion channels, and disease A. Glutamate excitotoxicity and potential protective effects of mGluRs Glutamate is the most abundant neurotransmitter that mediates excitatory actions in the vertebrate CNS. It was established as a neurotransmitter in the 1950s.

At about the same time, its neurotoxicity was also revealed. While Ca influx through activated NMDA receptors is necessary for normal cellular functions and cell survival, over-activation of NMDA receptors and thus overload of intracellular calcium is a signal for cell death. Excitotoxicity is a hallmark for many neurological diseases. mGluRs can modulate the Purves et al., Neuroscience, Fig 6.6 amount of glutamate release, so they have been implicated to be protective against excitotoxicity.

Drugs targeting mGluRs are being developed towards treatment of many human disorders such as autism, chronic pain, drug addiction, anxiety, schizophrenia, etc.

Neurotransmitter:

mGluRs:

Hayashi, 1954 (proposed…)

Sladeczek et al., 1985

Curtis et al., 1959 (showed…)

1950s

1960s

Lucas and Newhouse, 1957 (demonstrated Glu neurotoxicity)

Nicoletti et al., 1986

1970s

1980s

multiple iGluRs Illustrated by Yong Lu, Ph.D.

B. Neurotoxins (e.g. tetrodotoxin, botulinum toxin) Lots of biological neurotoxins target ion channels. Tetrodotoxin blocks voltagegated Na channels, and thus stops any Na channel-dependent events such as neurotransmission from occurring. Botulinum toxins have several types, all of which bind and destroy proteins essential for neurotransmission, especially acetylcholine release at neuromuscular junctions. Though botulinum toxins are the most poisonous to humans, in Botox therapy, a small amount of botulinum toxin is injected under the skin to numb muscles and remove wrinkles. A small trace amount of tetrodotoxin is contained in a kind of food “Fugu” to make the “delicious and delicate” taste—dosage is the key.

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Yong Lu, Ph.D., Synaptic transmission III, MN

Neurotoxins

Produced by

Effects

Agitoxin Apamin Batrachotoxin Botulinum toxin Charybdotoxin Cobrotoxin Crotoxin Dendrotoxin Iberiotoxin Kaliotoxin Kurtoxin Latrotoxin Margatoxin Noxiustoxin Philanthotoxin Phoneutriatoxin Phrixotoxin SNX-482 Taicatoxin Tetrodotoxin

Scorpion Honey bee Poison Arrow Frog Bacteria Scorpion Cobra S. American Rattlesnake Green Mamba Scorpion Scorpion South African Scorpion Black Widow Spider Scorpion Scorpion Predaceous Wasp Banana spider Chilean fire tarantula African Tarantula Australian Taipan snake Pufferfish

Blocks potassium channels Blocks potassium channels Prevents sodium channels from closing Blocks acetylcholine release Blocks potassium channels Blocks nicotinic receptors Reduces acetylcholine release Blocks voltage-gated potassium channels Blocks potassium channels Blocks potassium channels Blocks calcium channels Enhances acetylcholine release Blocks potassium channels Blocks sodium channels Blocks glutamate receptors Slows sodium channel inactivation Blocks potassium channels Blocks calcium channels Inhibits voltage-gated calcium channels Blocks sodium channels

C. synaptic transmission in myasthenia gravis Morphology of NMJ in MG patients â&#x20AC;˘

Normal functional motor nerve terminals, in terms of the size of the presynaptic terminal, numbers and locations of synaptic vesicles, active zones, and voltage-gated calcium channels, etc. (in contrast, in Lamber-Eaton myasthenic syndrome, presynaptic VGCCs are reduced, causing muscle weakness).

â&#x20AC;˘

Abnormal muscle cells: less number of nicotinic AChRs, shallower junctional folds, and widened synaptic cleft. These changes (especially reduced nAChRs) lead to smaller synaptic current (the current induced by the flow of ions through the channels).

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Yong Lu, Ph.D., Synaptic transmission III, MN

Treatment of MG MG is an autoimmune disease (antibodies against nAChR are produced in the patientâ&#x20AC;&#x2122;s immune system). Ptosis (severe drooping of the eyelids) is characteristic of MG. Treatment by drugs edrophonium or neostigmine, both of which are AChE inhibitors.

Inhibition of AChE causes prolonged activity of ACh in the synaptic cleft and thus prolonged activation of nAChRs, resulting in larger end-plate potential (EPP) and higher probability of action potential generation in muscle cells.

Sample question Which one of the following lists the molecules involved in the cyclic AMP (cAMP) pathway in the correct order?

A. transmitter, G-protein, G-protein-coupled receptor, adenylyl cyclase, cAMP, cAMP-dependent protein kinase, target protein B. transmitter, G-protein-coupled receptor, G-protein, cAMP, adenylyl cyclase, cAMP-dependent protein kinase, target protein C. transmitter, G-protein-coupled receptor, G-protein, adenylyl cyclase, cAMP-dependent protein kinase, cAMP, target protein D. transmitter, G-protein-coupled receptor, G-protein, adenylyl cyclase, cAMP, cAMP-dependent protein kinase, target protein E. transmitter, G-protein, G-protein-coupled receptor, cAMP, adenylyl cyclase, cAMP-dependent protein kinase, target protein Answer: see the first page of this lecture note

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Yong Lu, Ph.D., Synaptic Integration, MN

Synaptic Integration Learning Objectives 1. Compare functional zones of a neuron, explain why action potentials are triggered at the spike initiation zone 2. Compare spatial summation with temporal summation of EPSPs 3. Be familiar with some bioelectricity terms: membrane resistance, capacitance, current, Ohmâ&#x20AC;&#x2122;s Law 4. Describe the contribution to synaptic integration of passive properties of neurons: size principle, distance principle 5. Describe the contribution to synaptic integration of active properties of neurons 6. Explain how EPSP and IPSP are integrated 7. Describe the basic features of miniature spontaneous synaptic responses 8. Explain how presynaptic GPCRs can change synaptic transmission by affecting Ca and K channels 9. Describe postsynaptic GPCR-mediated modulation of synaptic transmission 10. Define the following terms: synaptic integration spatial summation length constant size principle miniature synaptic response

spike initiation zone temporal summation time constant distance principle synaptic modulation

Answer to the practical question at the end of this lecture note: E

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Yong Lu, Ph.D., Synaptic Integration, MN

Each neuron receives numerous (ranging from a few, to hundreds, and to thousands) synaptic inputs. Synaptic inputs come with many different forms and impinge on postsynaptic cells on multiple locations (mostly on dendrites, but common on cell bodies and axonal terminals).

Although there are numerous inputs to a single neuron, the output of a neuron is simple and straightforward. The neuron just needs to make one decision: to fire an action potential or not to fire an action potential. If the neuron fires, it will make some impact on the targets the neuron innervates; otherwise, little or no impact.

I. Synaptic integration: introduction A. Definition of synaptic integration: The process by which the spike initiation zone (SIZ) of a neuron combines all synaptic inputs and makes a decision whether to fire or not to fire an action potential.

B. Spike initiation zone (SIZ) 1. SIZ, also called Trigger Zone, is the initial segment of axon hillock. In the majority neurons, this segment comes off the cell body. In some cases, this zone comes off dendrites.

2. SIZ has the highest density of voltage-gated Na channels, so the action potential threshold is the lowest (most negative).

3. Usually, several excitatory inputs must summate in order to exceed threshold for action potentials.

Illustrated by Yong Lu, Ph.D.

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Yong Lu, Ph.D., Synaptic Integration, MN

C. Summation of excitatory postsynaptic potentials (EPSPs) 1. Spatial summation: the integration of EPSPs generated at more than one synapses on the same cell. The summation is not totally linear even if the EPSPs occur at the same time (the summed PSP is not equal to, but is smaller, than the mathematical addition of the individual EPSPs).

2. Temporal summation: the integration of EPSPs generated in rapid succession at the same synapse. These synaptic inputs arrive the SIZ in sequence and with overlap in the time course of the EPSPs. Again, the summation is not totally linear.

3. IPSPs can also summate in the same manner. But keep in mind that IPSPs in most neurons cause membrane hyperpolarization.

Note: these terms (spatial and temporal summation) are for illustration and theoretical interpretation purposes. In reality, the two processes cannot be completely separated.

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Yong Lu, Ph.D., Synaptic Integration, MN

D. Contribution of passive properties of dendrites to synaptic integration 1. Some general rules regarding passive properties: 1). Passive properties (resting membrane resistance, capacitance, axial resistance) are relatively constant for a particular neuron.

2). Larger neurons generally have lower resting membrane resistance (R), larger capacitance.

2. Size principle: based on Ohmâ&#x20AC;&#x2122;s Law (V=IR), smaller cells have larger EPSPs than larger cells in response to the same synaptic input.

Illustrated by Yong Lu, Ph.D.

3. If the dendritic membrane is not leaky (the inside is perfectly insulated from outside), EPSP at the soma will be the same as that at the input site. However, the dendritic membrane is leaky; therefore, there is decay in EPSP from the input site to the cell body.

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Yong Lu, Ph.D., Synaptic Integration, MN

4. Distance principle: The farther the input from the SIZ, the smaller the EPSP and its impact at the soma.

Illustrated by Yong Lu, Ph.D.

E. Contribution of active properties of dendrites to synaptic integration 1. Assuming no active conductances (voltage-gated ion channels) on dendrites, decay of EPSP is inevitable. This may be the case for motor neurons in the spinal cord.

2. However, in many other neurons (e.g. in the cortex), voltage-gated ion channels exist on dendrites. Activation of these channels (esp. Na and Ca channels) by membrane depolarization (e.g. by EPSP itself) introduces inward current into dendrites, counteracting decay of EPSP.

Illustrated by Yong Lu, Ph.D.

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Yong Lu, Ph.D., Synaptic Integration, MN

F. Integration of EPSP and IPSP IPSP, when overlapping with EPSP in time, cancels out EPSP partially or completely, reducing the probability of spike generation.

II. Synaptic modulation A. Factors subject to change (modulation, plasticity) 1. Transmitter molecules are released spontaneously and randomly. This release is action potential-independent.

2. Most of time, this transmission is due to only one vesicle release. The postsynaptic response is called a miniature synaptic event, or a “mini”.

3. A “mini” is the elementary unit (quantum) for synaptic transmission, termed quantal size. It is very small in amplitude, but relatively stable at a specific synapse (i.e., not very plastic or flexible under normal conditions).

4. An evoked synaptic response (in response to one presynaptic action potential) is integer multiple of minis. By comparing the amplitude (more precisely the charge) of an evoked response to that of a mini, the number of vesicles released due to the presynaptic action potential can be estimated. This process is called quantal analysis.

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Yong Lu, Ph.D., Synaptic Integration, MN

Quantal release: Quantal release was initially discovered in NMJ. Without any stimulation, motor neuron terminal release single vesicle resulting in MEPP (miniature end plate potential, about 0.4 mV in amplitude). When stimulated under low Ca concentration (to reduce release probability), the motor axon release vesicle(s) and muscle cell responds producing EPPs. EPPs vary in size, but the amplitudes of EPPs are integer multiples (0.4, 0.8, 1.2 mV etc.) of average MEPP.

7

Yong Lu, Ph.D., Synaptic Integration, MN

B. Synaptic modulation

Illustrated by Yong Lu, Ph.D.

1. Many factors associated with synaptic transmission are subject to change, including but not limited to, number of transmitter vesicles released per presynaptic action potential, the vesicle fusion process, number of transmitter receptors, and configuration (state) of the receptors. GPCRs mediate most of the modulations.

2. Presynaptic modulation of Ca channels: inhibition of Ca channels by GPCR reduces Ca ion entry into the presynaptic terminal, and consequently reduces the amount of transmitter release and the size of postsynaptic potentials. This is the most common mechanism for synaptic modulation.

Illustrated by Yong Lu, Ph.D.

3. Presynaptic modulation of K channels: inhibition of K channels by GPCR slows down the falling phase of an invading presynaptic action potential. Widening of the action potential allows Ca channels to be activated for longer time. This increases the amount of transmitter release and the size of postsynaptic potentials.

8

Yong Lu, Ph.D., Synaptic Integration, MN

4. Postsynaptic modulation: GPCRs can also change the responsiveness of postsynaptic receptors in either direction (enhancement or reduction), and thus change the size of postsynaptic potentials.

Illustrated by Yong Lu, Ph.D.

9

Yong Lu, Ph.D., Synaptic Integration, MN

One great example is the sedative agents (or tranquilizers) used to reduce anxiety or induce sleep. Many such agents (regional anesthesia: barbiturates, benzodiazepine, zolpidem, propofol, etc.) are modulators of GABAaRs, causing enhancement of the activity of these receptors. In contrast, ketamine (general anesthesia) reduces NMDAR responses (also enhances .

One final note for the term of Modulation: a term used to describe the actions of neurotransmitters that do not directly evoke postsynaptic potentials but modify the cellular responses by altering channel properties, particularly K and Ca channels. The meaning of this term is broad, evolving, and defined differently under different conditions.

10

Yong Lu, Ph.D., Synaptic Integration, MN

Food for thought: Tripartite synapse: glial cells are believed to be the supporting cells in the CNS, and they do not participate in neural signaling. Recent works, however, have demonstrated that astrocytes can release neurotransmitters upon stimulation, and they can also respond to neurotransmitters released from nerve terminals due to the presence of postsynaptic receptors on astrocyte membrane. Therefore, astrocytes could participate in neural signaling via formation of a tripartite synapse (3 components: presynaptic terminal, postsynaptic cell, and astrocyte). The mechanisms and functions of such synapses await further investigation.

Sample question Where is the spike initiation zone located in a neuron?

A. the 6th node of Ranvier B. distal dendrites C. axonal terminal D. nucleus E. initial segment of axon hillock Answer: see the first page of this lecture note

11

SYNAPTIC PLASTICITY Alexander Galazyuk, Ph.D. Objectives: In the end of this lecture students will be able to: 1 describe different forms of synaptic plasticity 2 explain the difference between short-term and long-term plasticity 3 describe neural mechanism underlying short-term synaptic facilitation and depression 4 describe neural mechanism associated with long-term potentiation (LTP) and long-term depression (LTD) and their relationships to learning/memory Synaptic plasticity (overview) Brain plasticity refers to the ability of the nervous system to change in reaction to environmental diversity. These changes occur at many levels in the nervous system ranging from molecular events to behavior. Here we will mainly talk about synaptic plasticity, the activity-dependent changes in synaptic transmission varying in time scale from milliseconds to years. Synaptic plasticity has been suggested to form the neurochemical foundations of learning and memory.

1. Short-term synaptic plasticity â&#x20AC;&#x201C; Activity-dependent strengthening or weakening of chemical synapses which lasts for a few minutes.

Synaptic facilitation is a synaptic strengthening when two or more action potentials invade the presynaptic terminal separated by a few milliseconds (see figures below). This plasticity is Ca++dependent. Upon action potential invasion of the presynaptic terminal, Ca++ enters the terminal very fast, whereas the mechanisms of removing Ca++ from the terminal are much slower.

Therefore if two or more action potentials invade the terminal within the time course of milliseconds, Ca++ builds up in the terminal. An excessive amount of Ca++ inside the terminal causes more neurotransmitter to be released when a subsequent action potential invades this terminal.

Fig.1

Fig.2

Synaptic depression is a synaptic weakening when multiple action potentials invade the presynaptic terminal within several milliseconds (Fig.3). The main cause of synaptic depression

1

is the depletion of a pool of available synaptic vesicles.

Fig.3 Synaptic potentiation and augmentation are other short-term synaptic plasticity phenomena which are known to elicit after repeating synaptic activity. Both the synaptic potentiation and augmentation are strengthening synaptic transmission via Ca++-dependent mechanisms. The time scale of this strengthening, however, is much longer than synaptic facilitation.

Augmentation works over the time period of a few seconds, whereas potentiation lasts from tens of seconds to minutes. The synaptic mechanisms underlying these phenomena are largely unknown.

2. Long-term synaptic plasticity is long-lasting strengthening or weakening known as longterm potentiation (LTP) and long-term depression (LTD). These changes can last from hours to years. Both LTP and LTD describe the direction of changes in synaptic transmission but does not link to specific underlying mechanisms. In fact different molecular mechanisms can be responsible for LTP and LTD at different synapses in the brain. LPT and LTD have been most studied in the hippocampus and are responsible for the formation of new memories. a. long-term synaptic plasticity in hippocampus Induction of LTP in hippocampus

2

Fig. 4

Fig. 5

High frequency stimulation of the pathway 1 makes response of hippocampal neuron to the same stimulus intensity much stronger (Fig.6). This change may last for days to months (Fig.7).

Fig. 6

Fig.7

Molecular mechanisms underlying LTP in hippocampus

Fig. 8

3

During high frequency stimulation, strong depolarization causes â&#x20AC;&#x153;silentâ&#x20AC;? NMDA receptor to be permeable for Ca2+ via removing Mg2+ block from the receptor (Fig.8). This leads to LTP. Signaling events underling LTP (Fig.9) Ca 2+ entering through the NMDA receptor and activates protein kinases.

This can cause LTP by: -

-

-

increasing the effectiveness of existing postsynaptic AMPA receptors via phosphorylation of existing AMPA receptors (early phase of LTP) stimulating the insertion of new AMPA receptors (late phase of LTP) increasing of the presynaptic neurotransmitter release

Fig.9

Blocking of protein synthesis abolishes the late phase of LTP (Fig.10)

Fig.10

Induction of LTD in hippocampus In contrast to LTP which requires high-frequency stimulation to be induced, the LTD was found to be triggered at low stimulation rate (about 1 stimulus/s) (Fig.11).

4

Fig.11 Molecular mechanisms underlying LTD in hippocampus LTD occurs when a synapse is stimulated at low rate (one stimulus/second) for a period of several minutes. This stimulation depresses the EPSP at the synapse for several hours.

Signaling events underling LTD (Fig.12) - Note that both LTD and LTP in the hippocampus are triggered by intracellular Ca 2+ concentration change in the spine (small increase for LTD, large increase for LTP) - under weak depolarization only a few NMDA receptor channel are unblocked (Mg2+ is out) which causes small Ca2+ influx through the channel - low concentration of the internal Ca2+ activates protein phosphatases, (during LTP the kinases are activated instead) - protein phosphatases dephosphorylate AMPA receptors restricting their efficiency (probability of channels opening becomes lower, which causes LTD) Fig.12 Responses of individual neurons in human hippocampus to old (familiar) stimuli are stronger than to new (unfamiliar) stimuli.

Important to understand: For both LTP and LTD we refer to changes occurred at a single synapse. Therefore an individual neuron can â&#x20AC;&#x153;memorizeâ&#x20AC;? an enormous amount of information because each neuron typically has hundreds or even thousands of synapses.

b. long-term synaptic plasticity in cerebellar neurons (Purkinje neurons) In contrast to hippocampal LTD that are triggered by a low stimulation rate, the cerebellar LTD

5

can be induced by two independent inputs on Purkinje neurons only when they are activated at the same time (Fig. 13,C).

Note: there is neither LTP in Purkinje neurons nor NMDA receptors.

Fig.13 -

Stimulation of climbing fibers causes activating of voltage-gated Ca2+ channels.

(Blocking of Ca2+ influx blocks LTD.) – signal #1 - Glutamate from parallel fibers activates AMPA receptors (depolarization due to an influx of Na+) - signal #2 - Glutamate from parallel fibers activates metabotropic receptors (second messenger – activating protein kinase C [PKC]) - signal #3 LTD occurs when all intracellular signals (#1,#2, and #3) occur at the same time.

The mechanism underling “weakening” of synapses on Purkinje cells during LTD is as following: the activation of all three signaling pathways (#1. #2, and #3) simultaneously leads to activation of PKC which triggers clathrin-dependent removal of postsynaptic AMPA receptors from the postsynaptic membrane. Smaller number of AMPA receptors in the postsynaptic membrane

6

makes postsynaptic response in this synapse to the subsequent inputs weaker (LTD).

Important to understand: Purkinje cells are inhibitory. Therefore, when their activity is suppressed by LTD, these neurons provide less inhibition to their target cells (the deep cerebellar nuclei), that makes these target cells more excited.

Self-test questions: 1. For both LTP and LTD we refer to changes occurred at: a. individual synapse b. entire neuron c. axon d. individual dendritic branch 2. Synaptic depression is most likely to be associated with: a. down regulation of AMPA receptors in a spine b. removing of Mg++ block from postsynaptic NMDA receptors c. accumulation of Ca++ in the synaptic terminal d. depletion of a pool of available synaptic vesicles

7

Somatosensory System: Peripheral Neurons

Somatosensory System: Structure and Function of Peripheral Neurons Jeffrey G. Mellott, Ph.D., adapted from Merri Rosen, Ph.D. LEARNING OBJECTIVES:

1. Characterize the four sub-modalities of somatic sensation 2. Compare the four types of cutaneous mechanoreceptors based on their response characteristics.

3. Describe the composition, physical location & arrangement, and function of both muscle spindles and Golgi tendon organs.

4. Describe and compare the information encoded by muscle spindles and Golgi tendon organs.

5. Describe the sequence by which muscle spindles are activated and how they send information to the CNS. 6. Describe the transduction of somatic information by peripheral sensory receptors.

7. Describe temporal and spatial discrimination of somatosensory input.

8. Explain the relationships between fiber size, myelination, and conduction velocity.

9. Explain how lesion to a single dorsal root will affect sensation in the innervated skin region.

10. Explain how sensory innervation of the skin surface, muscles and joints are specialized for providing a high-definition neural image of manipulated objects.

11. Define and explain the following Key Words: Dorsal root ganglia Trigeminal ganglia Somatosensation Discriminative touch Proprioception Dermatome Mechanoreceptor Meissner corpuscle

Merkel cell Ruffini ending Pacinian corpuscle Receptive field Muscle spindle Golgi tendon organ Joint receptors Two-point discrimination

Required reading: Chapter 9, Neuroscience 6th Edition, Purves (ed), Sinauer Press, 2017.

Image Acknowledgments: Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, Mooney RD, Platt ML and White LE (2017) Neuroscience, Sixth Edition. Sunderland, MA: Sinauer Associates.

Additional images by S. Sivaramakrishnan and M. Rosen.

1

Somatosensory System: Peripheral Neurons

SOMATOSENSORY SYSTEM: PERIPHERY Overview The somatic sensory system mediates a range of sensations: touch, pressure, vibration, limb position, heat, cold, pain.

These sensations are transduced by receptors within the skin or muscles and conveyed to different nervous system targets. The somatosensory system can be divided into functionally distinct sub-systems with distinct sets of peripheral receptors and central pathways: 1) Cutaneous mechanoreceptors mediate sensation of fine touch, vibration, pressure; 2) Proprioceptors are associated with muscles, tendons, joints, and sense position of limbs and other body parts in space; 3) Nociceptors are involved in pain sensation; 4) Thermoreceptors sense temperature.

Clinical Significance Clinical evaluation of patients routinely requires an assessment of the sensory systems to infer the nature and location of potential neurological problems. Knowledge of how the various sensory modalities are transduced, relayed, represented and processed to generate appropriate behavioral responses is essential to diagnosing and treating a wide variety of diseases.

Somatic sensation: arises from information provided by a variety of receptors distributed throughout the body.

There are four major sub-modalities of somatic sensibility: 1) Discriminative touch: recognition of size, shape and texture of objects and their movement across the skin.

2) Proprioception: the sense of static position and movement of the limbs and body.

3) Nociception: signaling tissue damage or chemical irritation, perceived as pain or itch.

4) Temperature sense: warmth and cold.

The four sub-modalities share a common class of sensory neuron: the dorsal root ganglion neurons. But, different dorsal root ganglion neurons have different specializations of their peripheral nerve terminals (the peripheral somatosensory receptors), and each modality is mediated by a distinct system of receptors.

2

Somatosensory System: Peripheral Neurons

Transduction of Somatic Sensory Information â&#x20AC;˘ Somatosensory afferents convey information from the skin surface to central circuits.

Somatic sensory receptors arise from cell bodies in dorsal root ganglia (or in the trigeminal ganglion), and send one axonal process to the periphery and the other into the spinal cord or brainstem. â&#x20AC;˘ Action potentials generated in afferent fibers by touch, pain, pressure etc in the skin or muscle propagate along the fiber, past the cell body in the dorsal root ganglia until they reach the terminals, which are located in the CNS.

Figure 1: Somatosensory afferents convey information from the skin surface to central circuits.

(A) The cell bodies of somatosensory afferent fibers conveying information about the body reside in the periphery, in a series of dorsal root ganglia (DRG) along the spinal cord. Those conveying information about the head also lie in the periphery, in the trigeminal ganglia.

(B) Pseudo-unipolar neurons in the DRG give rise to a peripheral processes that ramify within the skin or muscle and central processes that synapse with neurons in the spinal cord and higher levels of the nervous system.

From Purves, Fig 9.1

3

Somatosensory System: Peripheral Neurons

Sub-systems of the somatosensory system

Discriminative touch

Sensing the position of limbs and other body parts in space

Cutaneous mechanoreceptors

Proprioceptors

Nociceptors (pain) Thermoreceptors

skin

muscles, tendons, joints

everywhere

Pain and temperature

The somatosensory system can be divided into functionally distinct sub-systems with distinct sets of peripheral receptors and central pathways. The characteristics of the sensory afferents and peripheral somatosensory receptors affect the way somatosensory information is processed.

4

Somatosensory System: Peripheral Neurons

Types of Somatosensory Receptors Somatosensory receptors are the modified distal processes, sometimes called dendrites, of primary sensory neurons that have their cell bodies in dorsal root ganglia.

These distal processes may be encapsulated endings, or free nerve endings. It is these endings that receive sensory stimuli.

There are four main categories of somatosensory receptors: mechanoreceptors, proprioceptors, thermoceptors and nociceptors.

(1) Mechanoreceptors specialized to receive tactile information.

These receptors respond to mechanical deformation of tissue (stretch, touch, pressure, vibration). They are cutaneous receptors (found in the skin) and their behavior has best been studied in glabrous (hairless) portion of the hand (palm and fingertips). These regions of the skin surface are specialized for providing a high-definition neural image of manipulated objects.

Figure 2: The skin harbors a variety of morphologically distinct mechanoreceptors From Purves, Fig 9.5

5

Somatosensory System: Peripheral Neurons

There are four classes of mechanoreceptors in the skin: (a) Merkel cell afferents Slowly adapting fibers; account for ~25% of the mechanosensory afferents in the hand.

Enriched in fingertips, and are the only afferents to sample information from receptor cells located in the epidermis. Merkel cell afferents have the highest spatial resolution of all the sensory afferents â&#x20AC;&#x201C; individual Merkels can resolve spatial details of 0.5 mm. They are highly sensitive to points, ridges, and curvature; they process information about form and texture. (b) Meissner afferents Rapidly adapting fibers; innervate skin more densely than Merkel afferents, account for ~40% of mechanosensory receptors in the hand. Enriched in tips of dermal papillae adjacent to the primary ridges and closest to the skin surface. They are elongated receptors, and formed by a connective tissue capsule comprising lamellae of Schwann cells. Meissner afferents are much more sensitive that Merkels to skin deformation; however their receptive fields are larger than Merkels so they transmit signals with less spatial resolution. (c) Pacinian afferents Rapidly adapting fibers; make up 10-15% of mechanosensory innervation of the hand.

Located deep in the dermis or in subcutaneous tissue. They resemble a small onion, with concentric layers of membrane surrounding a single afferent fiber. Pacinian corpuscles adapt more rapidly than Meissners, are very sensitive â&#x20AC;&#x201C; they can respond to skin displacements as small as 10 nanometers. Their receptive fields are very large.

Pacinian corpuscles are well suited to detect vibrations transmitted through objects that contact the hand or are grasped. (d) Ruffini afferents Slowly adapting fibers; elongated, spindle-shaped, capsulated, and located deep in the skin, and in ligaments and tendons. The long axis of the corpuscle is oriented parallel to the stretch lines of the skin: Ruffini corpuscles are particularly sensitive to the cutaneous stretching produced by digit or limb movements, or movements of fingers. They account for ~20% of the mechanosensory hand receptors. Together with muscle receptors, Ruffinis provide information to the CNS about finger position and conformation of the hand.

6

Somatosensory System: Peripheral Neurons

7

Somatosensory System: Peripheral Neurons

The different types of information conveyed by cutaneous mechanoreceptors is illustrated by comparing the responses of different afferents as a fingertip is moved across a row of Braille letters. All the afferent types are activated by this stimulation, but the information supplied by each type varies. Merkel afferents clearly recognize the details of the Braille pattern; Meissner afferents supply a slightly coarser version of this pattern. Details are lost in the Ruffini and Pacinian afferents, because these responses have more to do with tracking the movement and position of the finger than with the specific identity of the Braille characters.

Figure 3: Simulation of activity patterns in different mechanoreceptor afferents in the fingertip. From Purves, Fig 9.6

Understanding somatic signals requires interpreting complex spatiotemporal stimulus patterns across the different types of mechanoreceptors. For example, stereognosis is the ability to identify an object by touch & manipulation. This requires convergence of information from the different types of receptors within higher cortical regions.

8

Somatosensory System: Peripheral Neurons

(2) Mechanoreceptors specialized for proprioception While cutaneous receptors provide information about external stimuli, proprioceptors (receptors for “self”) provide information about mechanical forces arising within the body itself, particularly from the musculoskeletal system. Proprioceptors provide detailed and continuous information about the position of limbs and other body parts in space.

The two best studied proprioceptors are the muscle spindle and the golgi tendon organ. (a) Muscle spindles Muscle spindles are found in most striated (skeletal) muscles. A muscle spindle consists of four to eight specialized intrafusal muscle fibers surrounded by a capsule of connective tissue. The intrafusal fibers are distributed within and in a parallel arrangement with extrafusal fibers of skeletal muscle, which are force producing fibers. Sensory afferents are coiled around the central part of the intrafusal spindle. When the muscle is stretched, tension placed on the intrafusal fibers activates mechanically gated ion channels in the nerve endings, triggering action potentials.

The muscle is innervated by Group Ia and Group II afferent axons.

•

The Group Ia afferents are myelinated axons with the largest diameter, they adapt quickly during changes in muscle length, and provide information about limb dynamics – velocity and direction of movement.

•

The Group II afferents produce sustained responses to constant muscle length and provide information about the static position of the limb.

Figure 4: Proprioceptors in the musculoskeletal system: Muscle spindle. From Purves, Fig 9.7

9

Somatosensory System: Peripheral Neurons

(b) The Golgi tendon organ The golgi tendon organ (GTO) is a mechanoreceptor Figure 5: Proprioceptors in the musculoskeletal system: Golgi tendon that is located in tendons and informs the central organ. From Purves, Fig 9.7 nervous system about changes in muscle tension.

The GTO is formed by branches of Group Ib afferents distributed among the collagen fibers that form the tendons. Each GTO is arranged in series with a small number of extrafusal muscle fibers. Taken together, the population of GTOs for a given muscle provides an accurate sample of the tension that exists in the muscle.

(c) Joint receptors In addition to muscle spindles and golgi tendon organs, proprioception also occurs from mechanoreceptors in and around joints. These joint receptors resemble many of the receptors found in skin, including Ruffini endings and Pacinian corpuscles. These joint receptors do not make a large contribution to sensing features such as limb position, but they do signal information about the position of fingers, for example.

(3) Thermal receptors and (4) Nociceptors Thermoreceptors sense temperature â&#x20AC;&#x201C; both heat and cold, while nociceptors respond to noxious stimuli, that result in a sensation of pain. Both receptor types are free nerve endings and are found in skin, muscles and joints and on internal organs.

(Nociceptors and thermoreceptors will be studied in detail in the lecture on Pain Mechanisms).

Fibers with encapsulated endings (mechanoreceptors) generally have lower thresholds (i.e., are more sensitive to sensory stimulation) than fibers with free nerve endings (nociceptors and thermoreceptors).

10

Somatosensory System: Peripheral Neurons

Somatosensory (Primary) Afferents Somatic sensory afferents differ in their response properties and can be classified based on a set of characteristics. These characteristics are: (1) Axon diameter (2) Size of receptive field (3) Adaptation during a stimulus (4) Selectivity in responses to different somatic stimuli.

These differences in response properties can arise from differences in the afferents themselves, or from differences in characteristics of peripheral receptor cells.

The largest diameter sensory afferents (Ia) supply the sensory receptors in muscles.

Smaller diameter fibers (A) convey information about touch/tactile system.

The smallest diameter fibers (A, C) supply information about pain and temperature.

Not shown in table: Proprioception: Golgi tendon receptors: axon type Ib.

Illustration by S. Sivaramakrishnan

Mixed nerve

C (IV) Nociceptor, Thermal Receptors A (III) Nociceptor, Thermal Receptors A (II)

Number of fibers

Figure 6: Relative conduction velocity and afferent axon type of mechanoreceptor and proprioceptor afferents.

Fiber size (Âľm) 0 Conduction velocity (m/s) 0

2

4

6 36

11

8

Cutaneous Mechanoreceptors, Muscle stretch some Muscle Stretch (spindle) A (I) (spindle), Golgi tendon receptors receptors

10

12 72

14

16 18 108 m/sec

Somatosensory System: Peripheral Neurons

Sensory Transduction Structure and function of somatosensory neurons Primary somatosensory neurons are generally pseudo-unipolar neurons, and are specialized to respond to one (and sometimes more) of many different types of stimuli â&#x20AC;&#x201C; e.g. touch, pain, temperature, pressure. The cell bodies of somatosensory receptor cells are located in the dorsal root ganglia ganglia (or in the trigeminal ganglion), which is outside the central nervous system. The peripheral axon innervates targets in the periphery (skin, muscle etc) from where it receives information about the particular sensory stimulus. Action potentials are generated in the nodes of Ranvier in the axon at the peripheral region, then travel down the peripheral axon towards the cell body, and into the portion of the axon that ends in the nerve terminal in either the spinal cord or other regions of the central nervous system.

Figure 7: Primary afferent fiber. Illustration by M. Rosen

12

Somatosensory System: Peripheral Neurons

The fundamental mechanism of sensory transduction – the process of converting the energy of a stimulus into an electrical signal – is similar in all somatic sensory afferents.

Figure 8: Conversion of somatosensory stimulus into transmitter release in primary afferent fibers. Illustration by S. Sivaramakrishnan

A stimulus alters the permeability of cation channels in the afferent nerve endings, generating a depolarizing current known as a receptor (or generator) potential. If the receptor potential is large enough, it reaches the threshold for action potential generation in the afferent fiber. The rate of action potential firing is roughly proportional to the magnitude of the depolarization, which is proportional to the magnitude of the stimulus (i.e. the intensity of pressure, pain etc).

• At the transduction site of the sensory neuron, the receptor potential is graded with stimulus magnitude.

• At the trigger zone in the axon, all-or-none action potentials are generated, riding on top of the receptor potential.

• Further along the axon, receptor potentials are not observed, but action potentials remain, travel to the nerve terminals of the sensory neuron, which are located in the spinal cord or other regions of the CNS, where they result in transmitter release.

• The larger the sensory stimulus, the larger the magnitude of the receptor potential, the higher the frequency and number of action potentials, and the greater the amount of transmitter release.

• Thus, by changing the amount of transmitter released from the sensory neuron nerve terminal, information about the duration and magnitude of the sensory stimulus (i.e. stretch, pressure, pain etc) is conveyed to the next neuron, which lies in the CNS. 13

Somatosensory System: Peripheral Neurons

In Figure 9 below, deformation of a mechanosensory afferent (a Pacinian corpuscle) leads to a stretching of the membrane of the afferent fiber, increasing the probability of opening stretch sensitive cation channels in the membrane. Opening the channels leads to depolarization of the afferent fiber (the receptor potential), which if large enough, produces action potentials (spike potential).

Figure 9: Transduction in a mechanosensory afferent. From Purves, Fig 9.2

(Generator potential = Receptor potential)

14

Somatosensory System: Peripheral Neurons

Temporal and Spatial Discrimination of Somatosensory Input 1. TEMPORAL DISCRIMINATION - Adaptation of sensory afferents Sensory afferents are differentiated by the temporal patterns of their responses to sensory stimulation. Some afferents fire rapidly when a stimulus is first presented, then fall silent with continued stimulation. Other afferents generate a sustained discharge in the presence of an ongoing stimulus. Rapidly adapting afferents (those that become quiescent during a continued stimulation) are thought to be effective in conveying information about changes in ongoing stimulation, such as those produced by stimulus movement. In contrast, slowly adapting afferents are better suited to provide information about the spatial attributes of a stimulus, such as size and shape.

Figure 10: Slowly and rapidly adapting mechanoreceptors provide different information.

From Purves, Fig 9.4

Somatosensory afferents: â&#x20AC;˘

Ruffini and Merkel are slowly adapting

â&#x20AC;˘

Meissner and Pacinian are rapidly adapting

(Refer to Figures 2 & 3 above for more on afferent types.)

15

Somatosensory System: Peripheral Neurons

2. SPATIAL DISCRIMINATION - Two-point discrimination The size of the receptive field and the innervation density determine the spatial accuracy with which tactile stimuli can be sensed.

The minimum inter-stimulus distance required to perceive two simultaneously applied stimuli as distinct is called two-point discrimination.

Figure 11: Receptive fields and the two-point discrimination threshold. From Purves, Fig 9.3

Two-point discrimination: How far apart must two stimuli be before you can sense them as separate?

Two-point discrimination is defined as the minimum inter-stimulus distance required to perceive two simultaneously applied stimuli as distinct.

Receptive fields and the basis of two-point discrimination Receptive fields of primary somatosensory afferents The receptive field is the area of the skin surface over which stimulation results in a significant change in the rate of action potentials. The size of the receptive field is a function of the branching characteristics of the afferent within the skin: smaller arborizations result in smaller receptive fields. There are systematic regional variations in the size of afferent receptive fields that reflect the density of afferent fibers supplying the area. The receptive fields in regions of dense innervation (fingers, lips, toes) are small compared to those in the forearm or back that are innervated by a smaller number of afferent fibers.

The size of the receptive field and the innervation density determine the spatial accuracy with which tactile stimuli can be sensed. A higher density of nerve endings gives a better spatial resolution of stimuli.

16

Somatosensory System: Peripheral Neurons

Two-point discrimination varies across the skin surface. For example, on the fingertips, two stimuli 2 mm apart can be distinguished, while on the forearm, the stimuli have to be at least 40 mm apart before they can be distinguished.

Figure 12 below shows the differences in two-point discrimination on the body surface.

Somatic acuity is much higher in the fingers, toes, and face that the arms, legs or torso.

Figure 12: Mean two-point discrimination thresholds. From Purves, Fig 9.3

Innervation is specialized for the requirements of specific body regions - e.g., face and fingers have dense innervation of cutaneous AND proprioceptive mechanoreceptors.

This yields both better spatial resolution and higher resolution of position information.

17

Somatosensory System: Peripheral Neurons

Self Test Questions 1) Which sensory function is conveyed by afferents with the fastest conduction velocity? a. Pain b. Proprioception c. Discriminative touch d. Temperature 2) Which statements are true?

– Merkel mechanoreceptors are slowly adapting – Pacinian afferents have small receptive fields – Muscle spindles detect muscle length – Golgi tendon organs are mechanoreceptors – The greater the amplitude and duration of stretch on a mechanoreceptor, the less neurotransmitter is released.

3) Group 1a afferents are good at? a. encoding changes in muscle length b. encoding constant muscle length c. encoding muscle tension d. encoding changes in temperature 4) Which body part has the highest somatic acuity? a. thigh b. upper arm c. upper lip d. forehead

18

Somatosensory Pathways I and II Rosen

Somatosensory Pathways I and II Merri Rosen, Ph.D. - Delivered in 2020 by Dana Peterson, Ph.D. LEARNING OBJECTIVES: 1. Characterize the dorsal column/medial lemniscus system and its role in discriminative touch, vibration and proprioception. Identify the neural components of this pathway and the organization of somatosensory cortex.

2. Identify topography (somatotopy) in the dorsal column/medial lemniscus system.

3. Describe methods for assessing sensory function.

4. Compare and contrast consequences of lesions to peripheral nerves versus dorsal roots versus different parts of dorsal column/medial lemniscus pathway.

5. Compare and contrast the anatomical and functional organization of the spinothalamic, spinoreticular, and spinotectal pathways, and understand their functional roles for different aspects of pain.

6. Identify topography in the anterolateral system.

7. Contrast the patterns of deficits associated with damage to nociceptive pathways at different levels of the nervous system.

8. Describe the pathway for visceral pain, and relate it to the perception of pain.

9. Describe anatomical and functional organization of the pathways from the trunk and limbs to the cerebellum for non-conscious proprioception.

10. Describe the anatomical and functional organization of the somatosensory pathways associated with the trigeminal nerve.

11. Contrast the deficits associated with damage to different parts of the trigeminal system.

12. Understand alternating hemianalgesia to integrate the somatosensory lectures and to correlate patterns of deficits with specific locations of lesions.

13. Define and explain the following Key Words: anesthesia dorsal (posterior) columns medial lemniscus fasciculus gracilis fasciculus cuneatus internal arcuate fibers ventral posterior lateral nucleus internal capsule

somatosensory cortex (SI) postcentral gyrus somatotopic organization homunculus Brodmannâ&#x20AC;&#x2122;s areas 3a, 3b, 1 and 2 pain vs. nociception crude touch fast pain slow pain

substantia gelatinosa dorsal root ganglion anterior white commissure anterolateral pathway (tract) spinothalamic pathway spinoreticular pathway spinotectal (spinomesencephalic) pathway

Somatosensory Pathways I and II Rosen

ventral posterior lateral nucleus intralaminar nuclei reticular formation periaqueductal gray anterior cingulate gyrus insula analgesia (vs. anesthesia) astereognosis agraphesthesia phantom limb Romberg test ataxia non-conscious proprioception

dorsal (posterior) spinocerebellar tract cuneocerebellar tract ventral spinocerebellar tract rostral spinocerebellar tract inferior cerebellar peduncle superior cerebellar peduncle nucleus dorsalis Clarke’s nucleus external cuneate nucleus spinal trigeminal nucleus and tract

spinal trigeminal nu. pars caudalis mesencephalic nucleus chief (principal, main) sensory nucleus ventral trigeminothalamic tract ventral posterior medial nucleus (of thalamus) jaw jerk reflex corneal reflex consensual response direct response trigeminal neuralgia alternating hemianalgesia

Recommended Readings: Neuroscience: 6th Edition, Purves (ed), Sinauer Press, 2017 Ch. 9-10

OUTLINE: Overview Somatosensory fibers branch as they enter the CNS There are three main groups of somatosensory pathways: Discriminative touch: dorsal column/medial lemniscal system Pathway Somatotopy Homunculus Somatosensory cortex Higher order processing Projections out of somatosensory cortex Phantom limb Assessing function • Two-point discrimination • Proprioception • Romberg test • Dermatome 2

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Pain and temperature: The anterolateral system Pain, temperature, crude touch peripheral fibers Fast pain and slow pain Pathways • Spinothalamic pathway • Spinoreticular (spinoreticulothalamic) pathway • Spinotectal (spinomesencephalic) Somatotopy Spinal cord lesions and dermatomes Sensory deficits • spinal cord • medulla • pons and above Pain and the thalamus Pain and the cortex Visceral pain and pathway Spinocerebellar pathways Dorsal spinocerebellar tract Cuneocerebellar tract Other spinocerebellar pathways (ventral, rostral) Lesions of the spinocerebellar pathways Trigeminal pathways Trigeminal nuclei • Spinal trigeminal nu.

• Chief trigeminal nu.

• Mesencephalic nu.

Topography in the trigeminal pathways Clinical issues • Reflexes: jaw jerk and corneal (blink) • Trigeminal neuralgia • Alternating hemianalgesia Review Questions

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The Somatosensory pathways – overview Somatosensory fibers branch as they enter the CNS Many sensory fibers branch to provide information to local spinal cord circuits and also to higher brain centers (see figure below). In the next couple lectures, we will follow the sensory information to higher centers for conscious perception and non-conscious modulation of movement.

Branching of somatosensory fibers entering the spinal cord. (Note that all 4 fiber types enter via the DRG on both sides, not as schematized here.)

Adapted from Haines, Fig 8-35.

There are three main groups of ascending somatosensory pathways: 1. The dorsal (posterior) column/medial lemniscus pathway carries information for discriminative touch, pressure, vibration and conscious proprioception.

2. Anterolateral pathways (spinothalamic pathways) carry information for pain & temperature as well as a “crude” sensation of touch.

3. Spinocerebellar pathways carry proprioceptive information to the cerebellum for motor coordination. This information does NOT reach consciousness via these pathways.

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Discriminative touch: Dorsal column/medial lemniscal system This system carries most of what we refer to casually as “touch”, excluding pain and temperature. Specific information (and the tools for assessment) include discriminative touch (two-point discrimination tested with calipers), “fine touch” (cotton ball), ability to sense pressure on the skin, vibration (tuning fork), and conscious proprioception (with eyes closed, patient reports position of limbs as they are moved by examiner).

Neural components: • receptors: information from encapsulated receptors and hair shafts.

•

1st order neuron: cell body in dorsal root ganglion. Central process (axon) enters the cord and ascends in the dorsal columns to synapse in the dorsal column nuclei.

Information from the lower body travels in fasciculus gracilis; information from the upper body travels in fasciculus cuneatus.

•

2nd order neuron: cell body in the dorsal column nuclei (nu. cuneatus and gracilis).

Axons cross midline as the internal arcuate fibers to form the medial lemniscus.

These axons synapse in the ventral posterior lateral nucleus (VPL) of the thalamus.

•

3rd order neuron: cell body in VPL. Axon projects through the posterior limb of the internal capsule, and then through the corona radiata to terminate in somatosensory cortex in the postcentral gyrus. Within the posterior limb of the internal capsule, body topography is maintained with axons for lower limbs traveling most caudally and for upper limbs traveling most rostrally (illustration of this later, in discussion of trigeminal system).

IMPORTANT: Lesions in the dorsal columns will lead to ipsilateral signs whereas lesions above the decussation in the medulla will lead to contralateral signs.

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We will use a schematic like this to map out several of the sensory pathways. Refer to this page for the labels and abbreviations (youâ&#x20AC;&#x2122;ll have a separate schematic, with room to write notes, for each of the pathways). (Illustration by BR Schofield, 2010).

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Dorsal column/Medial Lemniscus Pathway You will complete this figure in lecture.

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Somatosensory Pathways I and II Rosen (Illustration by BR Schofield, 2010).

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Somatotopic organization in the DC/ML pathways.

The dorsal column/ medial lemniscus pathway is organized topographically throughout its course.

Because this organization reflects the body surface, it is called somatotopic organization. The significance is that damage to a portion of the pathway produces deficits associated with a specific, and predictable, part of the body. In other words, knowing the detailed distribution of a deficit can give insights into the location of a lesion. You will become adept at correlating deficits and lesions as we go through this course. For now, begin thinking about how a lesion in, say, the right fasciculus gracilis would be manifest clinically.

Would the deficit affect the upper body or the lower body? (A: lower). Left side or right side? (A: right).

What would be different in a second patient who had a lesion that completely cut her right medial lemniscus (and nothing Somatotopy in the DC/ML pathway. Haines, Fig. 8-4. else)? Answer: Two main differences â&#x20AC;&#x201C; first, the deficit would be on the left side of the body (the fibers in the right ML carry information from the left side of the body. The pathway crossed the midline via the internal arcuate fibers). Second, the deficit would involve both limbs and the trunk.

The medial lemniscus carries lower body information ventrally with info from more rostral dermatomes carried more dorsally in the ML; this somatotopy shifts along with the shifting position of the ML in the pons, with lower body information now carried laterally (see figure above). This somatotopy continuous into the internal capsule and postcentral gyrus as illustrated, allowing for localization of fine touch.

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The Homunculus The somatotopic organization continues into the cerebral cortex.

This organization gives rise to a map of the body surface called a homunculus (technically, then, a homunculus could be drawn for each of the parts of the pathway; it it is often drawn only for cortex). The figure shows the homunculus in the postcentral gyrus. Note the location of body parts and think about the distribution of cerebral arteries.

The homunculus in cortex is disproportionate - areas of the skin with a greater density of receptors (like the fingers) have more cortical space dedicated to them. This is another factor (along with receptive field size) that determines two-point discrimination thresholds.

Homunculus in primary somatosensory cortex. Purves 9.11

Higher order processing The cortex combines information from different receptor types onto cortical neurons with complex properties to form â&#x20AC;&#x153;higher orderâ&#x20AC;? perceptions, allowing us to identify qualities such as size, shape, and texture. Sensory deficits resulting from somatosensory cortex lesions can include agraphesthesia (inability to identify letters drawn on the skin) and astereognosia (inability to name objects held against the skin). These deficits are quite different from analgesia (loss of pain and temperature sensation) and anesthesia (loss of pain, temp and fine touch) which describe losses due to lesions at lower levels (peripheral nerves to thalamus). You will hear more about conditions that include somatosensory deficits in a later lecture on higher order cortical functions.

Projections out of somatosensory cortex Primary somatosensory cortex encompasses Brodmannâ&#x20AC;&#x2122;s areas 3a, 3b, 1 and 2.

(There are differences between the areas, but we will not go into them.) Information obtained by the primary somatosensory cortex is sent to other cortical areas: e.g., to posterior parietal cortex for integration with other senses and the building of an internal representation of the body and the outside world; to motor cortex for the execution of voluntary movements.

Cortical cells in primary somatosensory cortex also project to subcortical levels (e.g., spinal cord dorsal horn, dorsal column nuclei, VPL). This descending pathway can modify the processing and flow of sensory information.

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Phantom limb Loss of a limb may lead to a “phantom limb”, a phenomenon in which the patient feels that the limb is still present. Presumably the cortical representation of the lost limb remains intact for a considerable period of time, and in this period the limb remains associated with the mental image of the body.

Assessing function of the dorsal column/medial lemniscus system Calipers are used to test two-point discrimination and a tuning fork can be used for vibration. Fine touch can be tested with a cotton swab.

Proprioception is tested by asking the patient to close her eyes and report limb position as the examiner moves individual limbs or digits. The Romberg test also assesses proprioception. The patient stands with eyes open and feet together, and the examiner assesses how much the patient sways. The patient then closes his eyes. If swaying increases, inadequate proprioceptive input is reaching the brainstem (with eyes open, the visual system was compensating for loss of proprioceptive input). The Romberg test is positive if swaying increases with eyes closed, indicating damage to dorsal column system. In contrast, vision cannot compensate for ataxia due to cerebellar deficits.

Tabes dorsalis is a condition associated with the tertiary stage of syphilis. It is characterized by slowly progressing degeneration of the dorsal columns (and, eventually, other pathways such as the optic nerves). A major symptom is ataxia, due to the loss of proprioception.

Recall that a dermatome is the area of skin supplied by a single dorsal root.

Dermatomes overlap, so damage to a single dorsal root causes a rather small area of sensory loss. Peripheral nerves generally contain sensory fibers associated with more than one dorsal root. Careful mapping of a deficit will allow you to determine whether the deficit matches the distribution of a peripheral nerve, or the distribution of dermatomes; the former indicates peripheral nerve damage, whereas the latter indicates damage to the dorsal roots or pathways within the CNS. Of course, the real world is more complicated than just peripheral nerve versus CNS. For example, in peripheral neuropathy, the longest axons are the most susceptible to damage and so the deficits are associated with the distal limbs. This is referred to as the “stocking and glove” effect.

Pain and Temperature: The Anterolateral System Anterolateral system (spinothalamics, etc) The anterolateral system conveys information about pain and temperature, as well as a crude sense of touch. Crude touch refers to a poorly-localized, poorly-identified sense that is not enough touch information to make up for a dorsal column/medial lemniscus problem.

Damage to the anterolateral system causes deficits in both pain and temperature sensation. Given the clinical significance of pain, the rest of the notes on this system will focus primarily on pain.

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Pain and temperature information from free nerve endings is carried to the spinal cord by A fibers (small, myelinated) or C fibers (unmyelinated). Both fiber types are thought to use substance P as a transmitter. Both types of axon can branch when they enter the cord. The branches can ascend or descend a few segments in the dorsolateral tract (a.k.a. tract of Lissauer) before terminating on second order neurons. The axons then terminate in laminae I and V (A-delta) and laminae I and II (C fibers) in the dorsal horn.

The A-delta fibers convey “fast pain”, which is sensed very quickly and has the quality of sharp, well-localized stabbing pain. In contrast, the C fibers convey “slow pain” which has a dull aching or burning quality and which is sensed with a noticeable delay (compared to fast pain). The A-delta fibers feed into the spinothalamic pathways while the C fibers feed mostly into the spinoreticular (and other) pathways.

Spinothalamic pathway - “fast pain”, i.e., sharp, well-localized stabbing pain. (This pathway is sometimes referred to as the “lateral spinothalamic pathway”.)

1st order neuron: A fibers with cell body in dorsal root ganglion.

2nd order neuron: Cell bodies in laminae I and V of dorsal horn. Axons cross midline in the anterior white commissure to the anterolateral aspect of the spinal cord and brainstem.

3rd order neuron: cell body in VPL. Axons of VPL cells project through the posterior limb of the internal capsule to terminate in somatosensory cortex in the postcentral gyrus, which is important for the localization of pain. NB: Axons of the spinothalamic and dorsal column systems are both in the VPL, but terminate on separate sets of relay neurons. Thus pain vs touch information remains segregated up to the level of cortex.

Spinoreticular (or spinoreticulothalamic) pathway - “slow pain”, dull, aching or burning pain. The pain is not well-localized. (This pathway is sometimes referred to as the “anterior spinothalamic pathway”.)

1st order neuron: C-fibers with cell body in dorsal root ganglion.

Higher order neurons: 2nd-order neuronal cell bodies are in lamina I and lamina II (also known as substantia gelatinosa) of the dorsal horn in the cord. This pathway is multisynaptic with no single locale for 3rd-order neurons, so we abandon that terminology here. The 2nd order neurons project to the supraspinal levels and to other spinal laminae, which then project up to the reticular formation (bilaterally). The contralateral portion of the projection crosses the midline in the anterior white commissure. From there information goes to the intralaminar nuclei of the thalamus.

These extra synapses to reach the thalamus take more transmission time, contributing to the slowness of the pain. These pathways are not as well organized somatotopically; slow pain is not well-localized.

Projections from the intralaminar nuclei of the thalamus travel through the internal capsule and corona radiata to reach multiple cortical areas, including the postcentral gyrus, insula and anterior cingulate gyrus. The latter 2 areas probably contribute to the affective (suffering) aspects of pain, whereas the postcentral gyrus is more important for accurate localization of pain.

Spinotectal (or spinomesencephalic) pathway is similar to the spinoreticular, except that the ascending axons terminate in the tectum of the midbrain (in periaqueductal gray and superior colliculus).

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Anterolateral system pathways (Illustration by BR Schofield, 2010).

You will complete this figure in lecture.

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Somatotopic organization of the anterolateral pathway The spinothalamic pathway is organized topographically throughout much of its course. The anterior white commissure looks quite small in the standard cross section, but of course the commissure is present through the entire length of the cord. The clinical significance is that a lesion of this commissure usually affects one or a few spinal levels. The deficit would be limited to the associated dermatome, and would be bilateral. A lesion, say, of the commissure from T3-T6 would cause a “ring” of diminished pain (and temperature) sensitivity around the chest. Pain sensation from lower levels would be unaffected. (Note: the deficits would include both pain and temperature sensations; clinically, we usually test and discuss only the pain).

Somatotopy in the ALS pathway. Haines, Fig. 8-6.

In the anterolateral cord, the ALS fibers are organized with sacral information carried most laterally. Information from successively more rostral dermatomes is carried in more medial fibers (see figure above).

In the posterior limb of the internal capsule, the fibers associated with the ALS travel along with those of the dorsal column/medial lemniscus system (we are focusing here on the fibers from the VPL, which go to the postcentral gyrus and account for localization of pain).

These fibers, then, show the same topography in the internal capsule as do the DC/ML fibers. A “capsular stroke”, which can lesion just a small portion of the internal capsule, can eliminate the sensory fibers associated with part of the body, leaving other fibers intact.

Knowing the topography can help localize the lesion. Of course, the information that reaches the postcentral gyrus is also organized topographically; recall the sensory homunculus described above. A lesion of the “arm” region of the postcentral gyrus can reduce a patient’s ability to localize a painful stimulus affecting that arm (this is discussed 13

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in more detail below). Note that the present discussion applies to the spinothalamic portion of the ALS, which is responsible for precise localization of pain and temperature.

Topography and localization are not so precise in the spinoreticular and spinomesencephalic pathways.

What are the differences between the pain pathways? One theory suggests that the spinoreticulothalamic system contributes to states of attention, awareness and levels of consciousness. Another theory suggests that this pathway is concerned with the emotive/affective aspects of pain sensation (remember the projections to the limbic system â&#x20AC;&#x201C; insula and anterior cingulate). One fact is clear: when the spinothalamic tract is cut surgically to alleviate pain, it is usually successful only for a short period of time (few months to a year). Gradually the pain will return. It is assumed that this return of pain is due to the redundancy in the nervous system (i.e., the multiplicity of pain pathways) and that perhaps the bilateral spinoreticulothalamic system becomes increasingly activated.

Sensory deficits Lack of pain is called analgesia. A sharp probe is used for testing. An important clinical tool for evaluating the nervous system is careful testing of both anterolateral and dorsal column/medial lemniscus systems: In the spinal cord: lesion of the anterior white commissure disrupts pain and temperature sensation bilaterally- that is, an entire ring of the body will be missing these sensations. Hemisection of the cord will cause contralateral loss of pain and temperature, and ipsilateral loss of discriminative touch.

In the medulla: medial lesions disrupt discriminative touch for the contralateral body whereas lateral lesions disrupt pain and temperature sensation for the contralateral body (review the locations of the pathways!).

In the pons and above: pathways conveying all modalities from the contralateral body travel together to the thalamus (VPL). Thus, small lesions cause hemianesthesia - loss of pain, temperature and discriminative touch for the contralateral half of the body (but see notes below about loss of pain).

Pain and the thalamus - lesions involving the ventral posterior thalamus can cause a period (usually months) of analgesia followed by chronic pain. This is known as thalamic pain syndrome, and is an example of â&#x20AC;&#x153;central painâ&#x20AC;? (pain that results from a problem within the central nervous system).

Pain and the cortex. Damage to somatosensory cortex (e.g., from a stroke) can reduce the ability to localize pain, but does not eliminate the ability to feel pain. Note that a stroke of MCA (middle cerebral artery) could knock out much of primary somatosensory cortex, but would leave anterior cingulate cortex intact (which, as you recall, is a target of the spinoreticulothalamic pathway).

Phantom Pain - pain that occurs in a phantom limb (more in a subsequent lecture).

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Surgical intervention for the treatment of chronic pain has not been very successful.

Surgical transection of pain pathways often produces temporary relief, followed by chronic pain that can leave the patient more disabled than before.

Visceral Pain is often perceived elsewhere as referred pain, which arises in viscera but is perceived in somatic areas. One common example is pain arising when the heart is not being adequately perfused with blood, which is perceived in the left arm and hand. This pain is likely conveyed to the cortex by neurons also concerned with cutaneous pain, thus the sensory overlap.

Additionally, there is a recently-described component of the DC/ML system that conveys visceral nociception. This is visceral pain that is non-referred. Here, visceral afferents with cell bodies in the DRG synapse on 2nd-order cells in the intermediate gray region of the spinal cord near the central canal. Their axons ascend NOT through the anterolateral system, but through the dorsal columns near the midline, and synapse in the gracile nucleus in the caudal medulla.

From there they behave MOSTLY like DC/ML cells: cross in the internal arcuate fibers and ascend in the medial lemniscus to synapse in the VPL of the thalamus. But finally, they project to areas of the insula, mediating suffering aspects of pain.

This pathway is relevant because it allows a midline myelotomy to be a sometimes effective therapy for visceral pains such as arise from cancers.

Transecting the axons in the medial part of the dorsal columns (where the 2nd-order axons ascend toward the gracile nucleus) can provide significant pain relief.

Pathway for visceral pain, a component of the DC/ML system.

Purves Box 10C.

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Spinocerebellar pathways The spinocerebellar pathways carry sensory (proprioceptive) information to the cerebellum, which requires this information for production of coordinated movements.

Damage to the pathways causes ataxia, or uncoordinated movements. Damage to these pathways does NOT eliminate conscious proprioception (remember, that was handled by the dorsal column system), so we say that the spinocerebellar pathways are carrying information for non-conscious proprioception. Non-conscious proprioception is associated with pathways to the cerebellum; conscious proprioception is associated with pathways to the cerebral cortex. Note that the Romberg test described above does NOT test for spinocerebellar dysfunction, as vision cannot compensate for cerebellar issues.

As described in a previous lecture, proprioceptive information is gathered by muscle spindles, Golgi tendon organs, and joint receptors. The primary afferent (i.e., first order) neurons have cell bodies located in dorsal root ganglia, and central processes that enter the spinal cord. Within the cord, there are numerous pathways for this information to be carried to the cerebellum. All the pathways include second orders cells in the spinal cord, whose axons terminate in the cerebellum on the same side. Two of the pathways are larger and most relevant clinically. These two pathways, dorsal (posterior) spinocerebellar tract and the cuneocerebellar tract, are described in detail, followed by a brief description of the other pathways.

The dorsal spinocerebellar tract carries information from the trunk and leg. The second order cells are located in Clarke’s nucleus (also known as nucleus dorsalis or dorsal nucleus of Clarke), which is present in the spinal cord from T1 to L2. Between T1 and L2, primary afferents enter the cord and synapse with a second order neuron in Clarke’s nucleus. Primary afferents that enter the cord below L2 must ascend in the fasciculus gracilis until Clarke’s nucleus is reached. The axons from the second order neuron in Clarke’s nucleus form the dorsal spinocerebellar tract. These axons enter the cerebellum via the inferior cerebellar peduncle.

The cuneocerebellar tract carries information from the upper trunk and arm. Primary afferents enter the cord and pass directly into the ipsilateral fasciculus cuneatus. The axons ascend to the ipsilateral external cuneate nucleus (also known as lateral cuneate or accessory cuneate nu.), in the medulla. Neurons of the external cuneate nucleus project to the ipsilateral cerebellum via the inferior cerebellar peduncle.

The “other” spinocerebellar pathways.

Their functions are presumably similar to the main spinocerebellar pathways, but they are much smaller and the consequences of their damage are unknown. These reportedly show up on board exams, so we feel compelled to say something about them. The ventral spinocerebellar tract carries information from lower trunk and leg. Proprioceptive axons enter the cord and synapse on cells around the border of the ventral horn; axons of the second order cells cross the midline, travel up the cord and brainstem contralaterally, enter the cerebellum through the superior cerebellar peduncle, and then cross back. The rostral spinocerebellar tract carries information from the upper trunk/arm. Second order cells are 16

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in the cord scattered rostral to Clarke’s nucleus (i.e., at the same relative location in the cord as the dorsal spinocerebellar neurons in Clarke’s nucleus which is more caudal); the second order axons ascend ipsilaterally to enter the cerebellum via the inferior cerebellar peduncle.

Spinocerebellar pathways (Illustration by BR Schofield, 2010).

You will complete this figure in lecture.

Lesions of the spinocerebellar pathways: Briefly, a lesion affecting the spinocerebellar tracts leads to “clumsy”, uncoordinated movements known as ataxia. The deficits are ipsilateral to the lesion. If the lower limbs are involved, the ataxia manifests as an “unsteady gait” with a tendency to fall toward the side of the lesion. We’ll discuss these deficits in more detail when we consider the cerebellum.

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Trigeminal Pathways Somatosensory input from the head includes the same three types of information that we’ve discussed for the body: discriminative touch (as a broad term including all types of info carried by DC/ML paths), pain and temperature, and proprioception. Once again, the different types are handled by pathways that are separate below the thalamus. Most of the sensory information is carried by the trigeminal nerve, which carries information from the face, oral and nasal cavities, cornea, meninges and cranial blood vessels. Recall that there are also small sensory components (General Somatic Afferent) of cranial nerves VII, IX and X. All this GSA information is processed by the trigeminal nuclei.

The trigeminal pathways V nerve: all three divisions - ophthalmic, maxillary and mandibular - carry all three types of information. All trigeminal axons enter the brainstem at mid-pons.

The trigeminal nuclei.

Three subdivisions: Chief (or “principal” or “main”) sensory nucleus - discriminative touch / conscious proprioception (comparable to the dorsal column/medial lemniscal system).

Spinal trigeminal nucleus and spinal trigeminal tract – • The nucleus has 3 parts. The most caudal part, “pars caudalis”, processes pain and temperature (comparable to the ALS in the spinal cord). Much of the pain information arises from CN V. Another part of the spinal V nucleus projects to the cerebellum (equivalent to the spinocerebellar pathways, processing nonconscious proprioception).

• The facial, glossopharyngeal, and vagus nerves also convey pain and temperature information from their areas to spinal V nucleus. Thus, spinal V nucleus receives input from cranial nerves V, VII, IX, and X. This illustrates an important point: information of a given type (e.g., nociceptive) can be processed by a particular cranial nerve nucleus regardless of the cranial nerve that transmits the information.

Mesencephalic nucleus – some reflexes. This nucleus is unique in that it is the one place where the cell bodies of primary afferent fibers are located within the central nervous system (all other cases have the cell bodies in peripheral ganglia, i.e., dorsal root ganglia or cranial nerve ganglia).

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The trigeminal pathways. (Illustration by BR Schofield, 2010) You will complete this figure in lecture.

Not shown: projections from trigeminal nuclei to â&#x20AC;˘ the cerebellum (from spinal V, equal to spinocerebellar paths) â&#x20AC;˘ reticular formation and then to thalamus (equal to spino-reticulo-thalamic path)

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Topography in the trigeminal pathways.

There is reportedly a topographic order within the trigeminal nuclei and within the ventral trigeminothalamic tract; however, accounts vary and we will not go into it.

The ventral trigeminothalamic tract is not well circumscribed, but travels adjacent to the fibers of the medial lemniscus. Of course, as these tracts reach the thalamus, fibers carrying information from the trigeminal system terminate medially (in VPM) and fibers carrying information from the body terminate more laterally (in VPL). Projections from VPM travel in the internal capsule (in the posterior limb adjacent to the genu) and then in the corona radiata to reach the lateral part (face area) of the postcentral gyrus. (Of course, some pain fibers from the trigeminal system also terminate in intralaminar thalamic nuclei, which project to insula and anterior cingulate cortex).

Topography of axons traveling within posterior limb of internal capsule: F=face, A=arm/upper extremity, T=trunk, L=leg/lower extremity.

Adapted from Haines Fig. 8-6.

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Some clinical issues Jaw jerk reflex. Tested by placing a couple of your fingers on the front of the patient’s jaw and tapping to stretch jaw-closing muscles. Normal response is a closing “jerk” (this is sometimes hard to see). This is a monosynaptic reflex.

Sensory and motor paths are both in trigeminal nerve; sensory link goes “through” mesencephalic V nucleus (where cell bodies are located) and terminates in motor V nucleus.

Corneal reflex. Touching one cornea (say, with a bit of cotton) normally causes both eyes to close.

Closing of the stimulated eye is called the direct response; closing of the opposite eye is called the consensual response. Sensory path: pain fibers in V ophthalmic division projecting to spinal trigeminal nucleus pars caudalis. Spinal V nucleus pars caudalis projects to the reticular formation, which projects bilaterally to the facial nucleus. Motor path: facial nucleus to orbicularis oculi to close lids. The motor and sensory limbs are linked by projections from spinal V nucleus to reticular formation to both facial nuclei. This reflex tests components of both V and VII.

Circuitry for jaw jerk reflex.

Illustration by M. Rosen, 2012.

Circuitry for corneal reflex.

Illustration by BR Schofield, 2010.

The most important issue with regard to CNS lesions is the spatial separation of the spinal trigeminal nucleus and tract from the rest of the trigeminal system. Lesions to the lateral medulla will interrupt pain and temp information from the ipsilateral face, while leaving discriminative touch pathways intact. A lesion in the lateral mid-pons would interrupt the chief sensory nucleus or the first order axons heading to this nucleus; however, this lesion would probably also knock out pain and temperature sensation because these fibers also enter at the mid-pons and must travel to the medulla via the spinal trigeminal tract. Thus, a lateral pons lesion is likely to eliminate BOTH discriminative touch and pain/temp sensation in the ipsilateral face.

Trigeminal neuralgia (tic douloureux) is a condition characterized by repetitive, transient intense stabbing pain in a region innervated by a branch of the trigeminal nerve. The pain is frequently elicited by stimuli that are normally non-painful (e.g., light touch of the cheek, chewing).

Alternating hemianalgesia - “alternating” means occurring on one side of the face and on the opposite side of the body. This condition results from a lesion in the lateral medulla, which interrupts the anterolateral pathways and the spinal trigeminal nucleus and tract.

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Review questions 1. How would you distinguish a peripheral nerve lesion from a dorsal root lesion?

2. For the dorsal column-medial lemniscus pathway, identify the following: a) the locations of first-, second- and third-order neurons; b) the location and level at which the pathway crosses the midline; c) the type of information carried; d) the nature of the deficit if the pathway is damaged.

3. Total destruction of the medial lemniscus on the right side of the medulla would lead to a deficit where?

4. In somatosensory cortex, the area representing the foot is supplied by what cerebral artery?

5. Information about discriminative touch is carried in which limb of the internal capsule?

6. Describe the distribution of analgesia following damage to: a) ventral white commissure of the spinal cord at the level of C7 b) right anterolateral tract at the level of T4 c) complete transection of the cord at L5 7. Which limb of the internal capsule carries pain and temperature information from the body?

8. For both anterolateral and dorsal column/medial lemniscus systems: a) what receptors are involved? (think back to earlier lectures!) b) what peripheral nerve fiber groups are involved? (keep thinking back to earlier lectures!) c) where are the 1st order cells? 2nd order cells? 3rd order cells? d) where (at what level of the neuraxis) does each pathway cross the midline? The axon of which order cell does the crossing?

9. Proprioceptive information from the right leg: a. reaches which side of the cerebellum? b. is relayed by which: Clarkeâ&#x20AC;&#x2122;s nucleus or external cuneate nucleus?

10. A patient has difficulty walking. How would you distinguish damage to the spinocerebellar pathways from damage to the dorsal columns?

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11. Which side of the body would show ataxia following damage to the left inferior cerebellar peduncle?

12. Describe the pathway for the corneal (blink) reflex.

13. Trigeminal information is sent to which nuclei in the thalamus?

14. Damage to the left spinal trigeminal tract will produce what deficit (describe nature and distribution of loss).

15. Which cerebral artery supplies the cortical area for sensation from the face?

16. Where are the cell bodies of the primary afferent neurons for the trigeminal nerve?

17. Where does trigeminal sensory information cross the midline?

18. Review the brainstem cross-sections in your atlas, and identify a level (section) and the region of the section in which a lesion could cause alternating hemianalgesia.

Branches of which brainstem blood vessel could be involved in such a lesion?

19. Which part of the internal capsule carries trigeminal sensory information?

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Image Acknowledgments: Haines, DE (2012) Neuroanatomy, An atlas of structures, sections, and systems.

Lippincott, Williams & Wilkins.

Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, White LE (2012) Neuroscience, 5th edition. Sunderland, MA: Sinauer Associates.

The Wellcome Collection (http://images.wellcome.ac.uk/) Netter Presenter Image Copyright 2003 Icon Learning Systems. All rights reserved.

Medical Neuroscience materials, NEOMED. Additional images by B.R. Schofield, 2010-11 and M. Rosen 2012-2014.

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Visual System I: The Eye Sam Crish, Ph.D. LEARNING OBJECTIVES: 1. Describe the anatomy of the eye, including blood supply, fundus exam, and the pathway light takes from the cornea to the retina and pigment epithelium in the posterior eye, including how light interacts with elements of the eye and how the eye can influence that light.

2. Explain how the central nervous system can modify the optics (e.g., control of pupillary diameter and shape of lens) and how pupillary aperture relates to depth of field.

3. Know the structural aspects of photoreceptors and relate to functional aspects of light transduction. Understand phototransduction within the eye.

4. Describe differences between rods and cones. Relate photoreceptor properties to the neural responses of light.

5. Describe the arrangement of photoreceptors, the presence/absence and role of convergence, and explain the functional implications of photoreceptor organization.

6. Explain the synapses between photoreceptors and bipolar cells, especially how glutamate release from photoreceptors is modulated by light and how this neurotransmitter influences bipolar cell activity 7. Define and explain the following Key Words: visible light cornea pupil anterior chamber posterior chamber iris lens macula lutea fovea vitreous humor retina choroid sclera optic disk optic nerve blind spot melanin glaucoma papilledema

macular degeneration cataracts lens accommodation refractive power ciliary muscle ciliary ganglion Edinger-Westphal nucleus Zonule of Zinn iris sphincter muscle pupillary constriction pupillary dilator muscles pupillary dilation nearsighted farsighted presbyopia depth of field photoreceptor cone rod

horizontal cell amacrine cell bipolar cell ganglion cell photopigment retinal

opsin protanopia deuteranopia melanopsin light adaptation dark adaptation

PREPARATION: Review material from anatomy courses (Human Development and Structure) on the eye.

Readings: Neuroscience: 6th Edition, Purves (ed), Sinauer Press, 2017 Ch. 11 I. INTRODUCTION Humans have a complex visual system, mediating many aspects of detecting and processing light information. Pathways underlying visual perception occupy a substantial part of our brains that mediate everything from neural sensation and perception to control of non-neural parts of the eye.

II. TRANSDUCTION OF LIGHT ENERGY A. Aspects of Light 1. Visible light is a form of electro-magnetic radiation that can be sensed by our eyes.

Our eyes can see light having wavelengths in the range 400 – 700 nanometers.

Our ability to distinguish colors is based on photopigments that are differentially sensitive to the wavelengths of light.

2. Light can be viewed as having wave-like features (e.g., frequency or wavelength) and particle-like features (behavior of photons). The brightness or intensity of light can be related to the number of photons striking photoreceptors.

B. Basic anatomy of the eye (Fig. 1) 1. The eye is a fluid filled sac with three layers. a. The outermost layer is the cornea (clear tissue that light can past through and has most of the refractive power of the eye, but whose shape is not changeable moment to moment) and sclera (tough opaque tissue – the “white” of the eye). b. The choroid is a highly vascular layer providing blood supply to the outer and middle layers of the retina - photoreceptors and bipolar cells c. The retina is the neural organ of vision. It contains neuronal and glial cells as well as blood vessels of the central retinal artery and vein. These supply the inner layers of the retina - the retinal ganglion cell (RGC) layer and nerve fiber layer (NFL). Depression in the retina is known as the fovea, the area of high acuity and color vision (more on that later).

2. Structures of the eye internal to the three layers. a. Pupil – aperture through which light enters the back of the eye

b. Iris – muscles that control pupil diameter c. Lens – crystalline structure that focuses light d. Zonules of Zinn – connect lens and ciliary muscle. Control shape of lens. d. Ciliary body/muscle – structure that makes aqueous humor and controls tension of the suspensory ligaments 3. Chambers of the eye The eye is divided into the anterior, posterior, and vitreal chambers a. Anterior chamber - between the cornea and iris. Contains a watery fluid (aqueous humor) that provides nutrients to the cornea and is involved in keeping proper intraocular pressure in the eye. b. Posterior chamber – between the iris and lens. Also contains aqueous humor, which is made by the ciliary body here and passes through the pupil into the anterior chamber c. Vitreal chamber – Behind the lens. Largest chamber of the eye. Contains vitreous humor which gives the eye much of its shape (it turns over very slowly, hence, changes in aqueous humor modulate intraocular pressure) C. Optical properties of the eye (Fig. 1) 1. Path of light through the eye a. cornea – pupil – lens – vitreous humor ‐ retina (more on pathway through the retina later) – pigment epithelium (dark layer of cells abutting the retina) 2. Modification of light by eye a. The optical image is inverted by path through the eye (left-right and up-down). b. The cornea and the lens bend light rays to focus image on the retina.

Figure 1. Cross-section of the human eye. The arrow shows the path of light through the optical apparatus. From Purves, Figure 11.1.

Focusing of light (see Figure 2) i. Refractive power is the degree to which an object (cornea or lens) can bend light rays, and is expressed in diopters. ii. Most refractive power is in the cornea, but the shape of the cornea is fixed, while the lens can change its refractive power. iii. Curvature of the lens alters bending of light rays: under parasympathetic control.

iv. Relaxed ciliary muscle, lens has less curvature. v. With contracted ciliary muscle, lens has more curvature. vi. Activity of ciliary muscle of eye is controlled by Edinger-Westphal nucleus in midbrain (part of cranial nerve III nuclear group), projecting to neurons of ciliary ganglion, projecting to ciliary muscle.

Figure 2. The mechanism of lens accommodation. When looking at a nearby target, the ciliary muscle contracts (blue arrows), releasing tension in the zonule and allowing the anterior surface of the lens to round up (blue arrow) owing to its own elasticity. When looking at a distant target, the ciliary muscle relaxes, and the unopposed tension in the zonule (red arrows) flattens the lens (red arrow). From Purves, Figure 11.2; Illustrations by M. Rosen.

c. The iris controls pupil diameter. i. Pupillary dilation allows more light into the eye, but decreases depth of field (Fig. 3). Dilation of pupil caused by contraction of pupillary dilator (radial) muscle of iris, under sympathetic control. ii. Pupillary constriction allows less light into eye, but increases depth of field (Fig. 3). Constriction of pupil caused by contraction of iris sphincter muscle, under parasympathetic control.

Pupillary dilator Constrictors Pupil

Pupillary constrictor .

Dilators Action of pupillary muscles

Figure 3. Pupil aperture and depth of field explanation

d. Positioning/movement of eyes.

Each eye is controlled by 6 external eye muscles, three pairs operating in roughly antagonistic fashion. (More detail within Eye Movements lecture.) e. Image focusing (Fig. 4) i. Nearsightedness (myopia). Light-focusing apparatus is too strong for shape of eye. Nearby images are focused correctly on the retinal surface, but distant images are focused in front of retina, blurring the retinal image.

ii. Farsightedness (hyperopia). Light-focusing apparatus is too weak for shape of eye. Nearby images are focused behind the retina, blurring the retinal image. Distant images are focused correctly on the retina. iii. Presbyopia. Loss of lens’s focusing ability with age. This is due to thickening of lens and loss of its ability to round. The ciliary muscles that act on the lens (via Zonule of Zinn fibers) are fine.

Figure 4. Defects in the optics of the eye. A-C. Defects in shape of the eye can affect focusing and vision.

D. Presbyopia: the loss of lens accommodation with age. From Purves, Box 11A.

D. Transduction by photoreceptor cells 1. Photoreceptors are located in the back of the retina. Light must pass through other retinal elements to reach photoreceptors (Fig. 1) 2. General Features of Retina (Fig. 5) a. Pigment epithelium • Absorbs stray light • Provides metabolic support for photoreceptors b. Two main photoreceptor types • Rods, Cones • Contain photopigments, which absorb photons o Photopigment = light-absorbing chromophore retinal (an aldehyde of vitamin A) which is coupled to an opsin protein

o The type of opsin tunes the wavelength sensitivity of the photopigment; different opsins across rods and cones c. Bipolar Cells d. Horizontal cells, amacrine cells e. Ganglion cells â&#x20AC;&#x201C; first cells to have action potentials in the retina

Figure 5. Cells and layers of the retina. Photoreceptors (rods and cones) receive light input. Horizontal cells and bipolar cells receive input from photoreceptors. The bipolar cells synapse onto amacrine cells and ganglion cells. Ganglion cell axons form the optic nerve which ascends to the thalamus. All cells in the retina prior to ganglion cells have graded potentials, while ganglion cells are the first in the circuit to have action potentials.

From Purves, Figure 11.5.

3. Functional properties of photoreceptors (Fig. 6). a. Transduction of light energy by photoreceptors: light hyperpolarizes photoreceptor b. Review anatomy of photoreceptors i. Arrangement of elements in photoreceptors; photopigments on membranebound discs in outer segment ii. Resting (dark) state: partial depolarization (-40 mV) maintained by cGMPactivated Na+ channels, elevated release of neurotransmitter (glutamate) iii. Absorption of light energy leads to G-protein-coupled processes, closure of Na+ channels, thus hyperpolarization iv. Hyperpolarization suppresses glutamate release (onto bipolar cells)

Figure 6. TOP (general process): Effects of light hitting photoreceptor: • Decreases cGMP concentration • Closes Na+/Ca2+ channels (gated by cGMP) • Hyperpolarizes cell • Less neurotransmitter released onto next cell in pathway (bipolar) Right (detailed process): 1. Photon absorbed by photopigment 2. 11-cis retinal converts to all-trans retinal 3. Activates intracellular messenger transducin 4. Activates phosphodiesterase (PDE) 5. PDE hydrolyzes cGMP 6. Lowers cGMP concentration 7. Closes Na+/Ca2+ channels 8. Less Na+/Ca2+ flowing in, leads to hyperpolarization 9. Hyperpolarization leads to less neurotransmitter (glutamate) release onto bipolar cell From Purves Figs 11.7, 11.8, 11.9

Figure 7. The cone photoreceptor: some of the physiological and chemical changes that occur in response to light. The transduction mechanism is the same as in rods, except for the photopigment used.

Purves Fig. 11.5; Illustrations by M. Rosen, 2013

c. Cones (comparison with rods) i. More concentrated in the center of the retina ii. Different shape: no membrane around outer section, have invaginations of cell membrane where photopigments are located (Fig. 7) ii. Operate at moderate to high levels of light, because 1) The change in current from one photon is very small, hard to distinguish from background noise. In contrast, rods produce a reliable response to a single photon of light. 2) Less saturation. This is because their light adaptation mechanism is more effective than that of rods. (Fig. 9A) iii. Quick return to baseline after light allows fast temporal response (Fig. 9A).

This is also because their light adaptation mechanism is more effective, and they return to baseline much faster than do rods. iv. Transduction mechanism the same v. Three different types of cones have different visual pigments (opsins).

These are sensitive to different parts of the visual spectrum (Fig. 8) vi. Cones mediate color vision: the relative activation of the cone photoreceptors is responsible for our perception of color vii. No convergence: one-to-one projection from cones to bipolar (Fig. 9)

Figure 8. Relative absorption spectra for rods and three types of cones. Comparison of activity in S, M, and L cones provides the basis for color vision. Scones contain a photopigment most sensitive in the blue range.

M-cones contain photopigment most sensitive in the greenyellow range. L-cones contain photopigment most sensitive in the red range.

Rods do not contribute to color vision. From Purves, Neuroscience, 2012, Figures 11.14.

Figure 9. LEFT: More saturation in rods than cones. As brightness of light flash increases, cone response returns to baseline quickly, while rod response is extended in time. Thus: 1. Cones can respond in bright light, while rods saturate (all channels closed) and can no longer respond in bright light.

2. Cones have fast responses and can signal closely-spaced events, while

rods canâ&#x20AC;&#x2122;t distinguish such events.

RIGHT: Convergence in rods, no convergence in cones. Thus: 1. Rods have poorer acuity but greater sensitivity to light 2. Cones have greater acuity but need more light to respond Purves et al., Neuroscience, 2012. Fig. 11.11, 11.12; Illustrations by M. Rosen, 2013

d. Adaptation i. Dark adaptation (Fig 10A): increased sensitivity due to reduced exposure to light - Photopigments that are bleached (retinal and opsin are dissociated) must recover. Involves reassociation of retinal and opsin, and reconstitution of photopigments onto outer segment membranous discs. Slow: 10’s of min. ii. Light adaptation: decreased sensitivity to ongoing light (Fig 10B) - Due to decrease in internal Ca2+: light closes photoreceptor cGMP-gated channels, less Ca2+ flow in. This causes: - increased cGMP - increased affinity of channels for cGMP - both make it less likely for channels to close. Thus, closure occurs only with brighter light. This is quick. More light – less sensitivity ‐ prevents saturation ‐ extends range of light intensity to which receptors can respond.

- Mechanism of light adaptation in cones is faster than that in rods.

Figure 10. Dark and light adaptation. Purves 2017 Fig 11.10

5. Photoreceptors and neural connections are distributed unequally in the retina (Figure 11). a. Macula lutea (“yellow spot”) is special region on retina b. Fovea is in central part of macula: depression/pit caused by lateral displacement of bipolar and ganglion cells for minimum optical distortion (Fig 11B) • avascular zone allows low optical distortion (Fig. 11B) c. Fovea contains cones, almost exclusively (Fig. 11A) • cones packed more densely in fovea than in periphery • low convergence from cones to bipolar cells to ganglion cells • results in higher spatial resolution for maximal acuity d. Visual acuity is highest in fovea. e. Regions away from fovea are rod-dominated (Fig. 11A).

• highly convergent (many rods onto one bipolar) • results in low spatial resolution but good detection of light (summation of the inputs of many rods into ganglion cells increases the likelihood of response) f. There are no photoreceptors at “blind spot”, where the optic nerve exits and the central retinal artery enters the eye. Know location of blind spots relative to fovea in each eye.

Figure 11. Arrangement of photoreceptors and neural elements in the eye.

A. Rods and cones are distributed differently in the eye. More densely-packed cones in the fovea (coupled with one-to-one relationship with bipolar and ganglion cells) provides highest level of visual acuity.

B. Arrangement of photoreceptors and neural elements in and around the fovea. In the center of the fovea (the foveola), the neural elements are shifted to the side so that light has a less obstructed path to the photoreceptors.

Purves Fig. 11.13.

The Fundus exam â&#x20AC;&#x201C; Image with ophthalmascope Can see features of retina, including major structures and microcirculation

E. Photoreceptor to bipolar synapse Photoreceptors release glutamate, however, unlike elsewhere in the CNS, it can have either an excitatory or inhibitory effect on the post-synaptic bipolar cell. The response depends on the type of glutamate receptor on the bipolar cell dendrites (Fig. 12)

Figure 12. Bipolar cells vary in their response to glutamate depending on the glutamate receptors they have. http://retina.anatomy.upenn.edu/~noga/fig%20ins.png

Review Questions: 1. Explain the mechanism by which the eye controls its ability to bend light rays. What happens in the process of aging that interferes with this?

2. Explain the process by which absorption of light by a rod leads to a receptor potential. What is the polarity of the receptor potential?

3. Describe two differences between rods and cones in the way that they respond to light.

4. Identify several differences that exist between visual processing in fovea and in the peripheral retina.

5. Explain why bipolar cells respond differently to glutamate.Â

Vision II. Sam Crish, PhD Lecture Objectives 1. Identify basic features of ganglion cells and their responses, including how retinal circuitry, including horizontal and amacrine cells, creates center-surround receptive fields of retinal ganglion cells to retinal circuitry and how retinal ganglion cells respond to light at different parts of their receptive fields.

2. Describe the functional organization of the central visual pathway (made up of two projections, retina to LGN and then LGN to V1) to visual cortex.

3. Understand how M and P pathways are organized in the retina, lateral geniculate nucleus, visual cortex, and beyond.

4. Describe basic features of the representation of visual stimuli in the lateral geniculate nucleus. Understand how visual information is organized in this area.

5. Describe basic features of the representation of visual stimuli in visual cortex.

6. Describe general features of the dorsal and ventral visual pathways from primary visual cortex. Relate to M and P pathways from the retina.

7. Terms: retinal ganglion cell horizontal cell amacrine cell on-center ganglion cell off-center ganglion cell M and P type ganglion cells visual cortex binocular zone monocular zone optic chiasm optic tract M and P pathways lateral geniculate nucleus

optic radiation area 17 calcarine fissure cuneus lingual gyrus Meyerâ&#x20AC;&#x2122;s loop stripe of Gennari orientation selectivity ocular dominance columns area V2 area MT area V4

II. Retinal projection A. General overview: system-wide features 1. Retinal ganglion cells (RGC) a. projection cells of the retina â&#x20AC;&#x201C; receive input from bipolar cells. Amacrine cells modulate these synapses through their terminations on the presynaptic bipolar cell terminal or the postsynaptic RGC dendrite. (Figure 1)

Figure 1. Neurons of the retina. (glia such as astrocytes, microglia, and Muller glia not shown).

b. Summary of RGC projection: Unmyelinated RGC axons course along the surface of the retina (recall the photoreceptors are closest to the rear surface of the eye) and collect at the optic disc, where they exit the eye, forming the optic nerve (Cranial Nerve II). The optic nerve enters the optic tract on the ventral surface of the brain. Some axons cross over to the contralateral side, some stay ipsilateral (more on this later), forming the optic tract. These RGC axons terminate in several subcortical targets, especially the lateral geniculate nucleus (LGN), the main thalamic relay for visual information. (Figure 2) Breakdown of RGC projection: i. Axons from throughout the retina collect and exit at optic disc - Retina and optic nerve (ON, Cranial nerve II) are central nervous system structures - Optic disc i. No photoreceptors (blind spot) ii. Entry point for central retinal artery - Each optic nerve contains all axons from one eye ii. Optic chiasm - Axons of ganglion cells in lateral hemiretina proceed ipsilaterally into optic tract - Axons of ganglion cells in nasal hemiretina cross through chiasm to contralateral optic tract iii. Optic tract contains crossed and uncrossed components

- Axons from ipsilateral temporal hemiretina and contralateral nasal hemiretina - Ganglion cells with axons in one optic tract all view the contralateral visual field - The majority of fibers in the optic tract terminate in the lateral geniculate nucleus

Figure 2. Major visual pathway. This pathway consists of retinal ganglion cells projecting from the eye to the lateral geniculate nucleus in the thalamus, and from the LGN to the primary visual cortex (AKA V1).

Both images from: http://arthistoryresources.net/visual‐experience‐2014/eye‐to‐brain.html

c. Retinal ganglion cell receptive fields i. Most RGCs have a “center-surround” receptive field.

- input from different photoceptors and inhibitory horizontal cells (which are inhibitory) on a bipolar cell create two “circles” that influence RGC firing. A smaller circle that is either excitatory or inhibitory surrounded by a larger annulus (donut) with the opposite effect. e.g., center is excitatory and surround is inhibitory, or vice versa. (Figures 3 & 4)

Figure 3. Mechanisms for center and surround responses in an ON-center/OFF-surround bipolar cell & retinal ganglion cell. Note that for OFF-center/ON-surround bipolar & ganglion cells, there is a different (excitatory) glutamate receptor on the bipolar cell. Adapted by M. Rosen from Purves et al, Neuroscience, 2008, Fig 11.21.

Figure 4. Retinal ganglion cell receptive fields. From Squire LR et al. [eds]: Fundamental Neuroscience.

San Diego, CA, Academic Press, 2002.

Horizontal cells and some amacrine cells mediate lateral interactions important in receptive field properties. This setup creates various increases or decreases of responses to different size, locations, and movement of light stimuli in the RGC’s receptive field (Figure 5).

Center surround receptive field of retinal ganglion cell is based on circuitry involving several photoreceptors, several horizontal cells, one bipolar cell, and the ganglion cell (Fig. 3). i. Center response is based on one or a few photoreceptors that connect directly to a bipolar cell, which in turn connects to the ganglion cell (Fig. 3A, B). ii. In an ON-center ganglion cell, a light stimulus that shines on the center of its receptor field (on the center cones) causes increased numbers of action potentials. (Fig. 14B). This is because light hyperpolarizes the photoreceptor (reducing the amount of neurotransmitter released onto the bipolar cell) BUT the bipolar cell has INHIBITORY glutamate receptors, and is thus released from some of the inhibition that would occur without light. iii. Surround response is based on many photoreceptors that surround the center photoreceptor (Fig. 14A). These connect to the center cone/bipolar cell via horizontal cells (Fig. 3C). iv. When a light stimulus shines on the OFF-surround part of the ganglion cell’s receptive field (i.e., on the photoreceptors that contribute to the surround), the net result is a decrease in the numbers of action potentials evoked by that ganglion cell (Fig. 14C). (The mechanism is that the horizontal cells alter neurotransmitter release from the center photoreceptor onto the bipolar cell.)

v. Since center and the surround have different effects on the ganglion cell’s discharge, light shining over the entire receptive field has relatively little effect.

Figure 5: Retinal ganglion cells respond optimally to contrast in their receptive fields. These receptive fields are represented here as circular patches on the retina; the receptive field is composed of “center” and “surround” regions with different responses to light. The figure shows the responses of an ON-center cell and off-center cell to five light stimuli falling on different parts of the receptive field (the stimulated portion of the receptive field is shown in very light yellow). The pattern of action potentials fired by the ganglion cell in response to each stimulus is shown. Duration of illumination is indicated by a bar above each record.

Left column. On-center cells respond best when the entire central part of the receptive field is stimulated (Left, 3). These cells also respond well, but less vigorously, when only a portion of the central field is stimulated by a spot of light (Left 1). Spot of Light in Surround (Left, 2) or ring of light Left, row 4) reduces or suppresses the cell firing, which resumes more vigorously for a short period after the light is turned off. Diffuse illumination of the entire receptive field (Left, Row 5) elicits no change in discharge because the center and surround oppose each other’s effects.

In OFF-center ganglion cells, the effects of light stimulation are opposite to those of ON-center ganglion Cells (Right column).

(From Squire LR et al [eds]: Fundamental Neuroscience. San Diego, CA, Academic Press, 2002.)

Additional factors concerning receptive field properties of retinal ganglion cells. a. Half of all ganglion cells are OFF-center/ ON-surround (the opposite of the ganglion cell described above). This means they are inhibited when light shines on their center cone, but are excited when light shines on cones surrounding the center cone. This occurs because the center cone is connected to a different type of bipolar cell, which uses a different type of glutamate receptor (an excitatory receptor) that has effects opposite to the inhibitory glutamate receptor in bipolar cells of the ON-center pathway.

This OFF-center bipolar cell in turn connects to an OFF-center/ONsurround ganglion cell. b. I’ve only showed you same-color light, but it can be more complicated then that (we’ll leave it as one-color light for the exam though ). When the center cone has one type of color sensitivity (e.g., green) and the surrounding cones have a different kind of color sensitivity (e.g., red), a ganglion cell becomes sensitive to color CONTRAST between the center and the surround of its receptive field. This is essential for color vision. c. M and P type ganglion cells: origin of functionally distinct pathways carried through to higher visual cortical areas i. M-type (magnocellular = large): • larger receptive fields • responds well to brief / moving stimuli • little or no color information • mediate motion and general spatial sensitivity ii. P-type (parvocellular = small) cells: • smaller receptive fields • respond well to more sustained stimuli • color-sensitive • mediate color/form vision

2. The visual field, the pathway to visual cortex, and primary visual cortex a. Projection of visual field onto retina b. Ascending pathway contains crossed and uncrossed components c. The optic tract, visual thalamus (LGN), and visual cortex contain an orderly, retinotopic representation of the contralateral visual field (Fig. 6)

Figure 6: The visual field has both binocular and monocular zones. Light from the binocular zone strikes the retinae in both eyes, but light from the monocular zone strikes the retina only in the eye on the same side. For example, light from a left monocular zone (temporal crescent) falls on only the ipsilateral nasal hemiretina and does not project upon the contralateral retina because the nose obstructs the path of light. The temporal and nasal hemiretinas are defined with respect to the fovea, the region in the center of the retina with highest acuity. The optic disc, the region where the ganglion cell axons leave the retina, is free of photoreceptors and therefore creates a gap, or blind spot, in the field for each eye. Each optic nerve carries all the visual information from one eye.

Each optic tract carries a complete representation of the contralateral one-half of the visual field. Thus, fibers from the nasal hemiretina of each eye cross to the opposite side at the optic chiasm, whereas fibers from the temporal hemiretina do not cross. In the illustration, light from the right half of the binocular zone falls on the left temporal hemiretina and right nasal hemiretina.

From Purves, Figure 12.4.

Figure 7. Organization of projections from the retina to the lateral geniculate nucleus. Axons from the right hemiretina of each eye project to different layers of the right lateral geniculate nucleus to create complete representation of left visual hemifield. Layers 1 and 2 form magnocellular pathway (M pathway), while layers 3- 6 form parvocellular pathway (P pathway). Layers 1, 4, and 6 receive input from the contralateral (left) eye that crosses in the optic chiasm. Illustration by M. Rosen, 2011-2016.

The lateral geniculate nucleus (Fig. 7) 1. Anatomy a. Located in caudal, lateral thalamus b. Six layers receive different inputs i. Ipsilateral vs contralateral input ii. M-type vs P-type retinal ganglion cells c. Highly organized inputs from the two retinae preserve topographic visual field representation.

2. Functional properties a. LGN layers maintain separate M and P channels, and ocular dominance patterns (input from each eye is segregated to different layers of neurons) b. Receptive fields are similar to retinal ganglion cells â&#x20AC;˘ center-surround â&#x20AC;˘ ON-center and OFF-center c. LGN has systematic representation of the two hemi-retinas, forming a systematic representation of the contralateral visual field

d. LGN neurons send a projection, the optic radiation (geniculo-striate or geniculo-calcarine pathway), which carries visual information to the primary visual cortex (V1) (Fig. 8)

Figure 8. (A) An overview of the visual fields and of the visual pathway from above. (B) The retinogeniculate and geniculostriate pathways in the sagittal plane. Input from the inferior visual field reaches the upper bank of the calcarine sulcus. Note the disproportionately large representation of the macula; the central 10 degrees of visual field space occupies about one half of the visual cortex. Adapted from Purves, 2017, Fig. ClinApplic 12; Illustrations by M. Rosen.

1. Axons of LGN cells project to Area 17, primary visual (striate) cortex a. Area 17 in occipital lobe b. Located along superior and inferior banks of the calcarine fissure, occipital pole 2. Neurons in dorsomedial part of LGN send axons to superior bank of calcarine fissure (cuneus) a. These LGN axons join the internal capsule, passing laterally and caudally over the inferior horn of the lateral ventricle, and underneath the parietal lobe b. These neurons carry information about the lower part of the contralateral visual field.

3. Neurons in ventrolateral part of LGN send axons to inferior bank of calcarine fissure (lingual gyrus) a. These LGN axons first sweep rostrally, into the white matter of the temporal lobe, passing over or in front of the inferior horn of the lateral ventricle. They then pass caudally to the lingual gyrus. The path these fibers take through the temporal lobe is called Meyerâ&#x20AC;&#x2122;s loop. b. These neurons carry information about the upper part of the contralateral visual field.

Primary visual cortex (Area 17) 1. Anatomy (Fig. 8) a. Extends from the occipital pole (representing foveal visual field) along superior and inferior banks of the calcarine fissure on medial part of cerebral hemisphere (representing more peripheral parts of visual field). b. Distinctive in fiber-stained material due to heavy myelinated optic radiation fibers in Layer IV. Called stripe of Gennari. Due to these stripes (or striations), visual cortex is also called striate cortex. c. Pattern of termination of geniculo-striate neurons i. Neurons from M- and P-type LGN layers project to different layers and sublayers in visual cortex (maintains segregation of M- and P-pathways) (Fig. 9). ii. LGN neurons responding to inputs from one eye terminate in patches that are mostly separate from terminations of LGN neurons responding to inputs from other eye. Different parts of visual cortex are thus dominated by inputs from one or the other eye (Fig. 19). d. Blood supply from posterior cerebral artery, except at occipital pole where collaterals of both middle and posterior cerebral arteries may overlap.

Figure 9. M and P layers in the LGN remain segregated, as they project to separate layers of visual cortex Area 17. Adapted from Purves, Fig. 12.13.

2. Functional properties and organization in visual cortex a. Primary visual cortex systematically represents visual field i. based on an orderly representation of the retina (but you should remember the visual field representation) ii. Macular representation at occipital pole is disproportionately large (central 10° of visual occupies about 50% of primary visual cortex) iii. upper visual field represented in lingual gyrus iv. lower visual field represented in cuneus v. peripheral retinal field (extrafoveal region) represented rostrally along calcarine fissure b. Analysis of visual features in visual cortex (Fig. 10) i Receptive field properties. Analysis of visual form depends on increasingly complex receptive field properties in visual cortex. (Fig. 10A). Additional classes of cells (not shown) respond to oriented bars that move in specific directions, or that appear in many parts of the receptive field. ii. Orientation selectivity. Many Area 17 neurons are responsive to spatially oriented contours of light or dark: e.g., bars or lines, rather than to spots of light. â&#x20AC;˘ Area 17 neurons differ in their preferred orientation of light or dark shapes (Fig. 10B,C).

•. This arises because neurons with concentric receptive fields located in slightly different locations converge onto a visual cortical neuron. (Fig. 10D).

• Orientation selectivity is organized in visual cortex (Fig. 19B).

Figure 10. (A) Unlike center-surround receptive fields in cells of the LGN that respond to spots of light (or dark), primary visual cortex (Area 17) contains many “simple” cells that respond to light (or dark) bars. (B) Receptive fields of several simple cells depict how they have different orientation selectivities. (C) A single Area 17 cortical cell responds best to a bar of a specific orientation. (D) Orientation-selectivity is created via convergence of LGN neurons with center-surround receptive fields (orange) onto a “simple” cell (purple) of visual cortex. Illustrations by M. Rosen; Purves et al, 2017, Fig. 12.6.

iii. Visual form and motion. M (motion/location) and P (color, form) type LGN neurons synapse on separate populations of cortical neurons (Fig. 9). Thus, M and P pathways remain largely separate throughout visual cortex. c. Ocular dominance. The response to stimulation of the two eyes is an important feature of visual cortical function and organization (Fig 11). i. Area 17 neurons are activated more strongly by stimuli in one eye or the other eye (= ocular dominance). ii. Area 17 is organized into adjacent groups of cells that respond best to one or the other eye. These are called ocular dominance columns, because they are composed of groups of cells extending from the cortical surface to the deepest cortical layers. Adjacent ocular dominance columns look at the same part of the visual field, but with different eyes.

iii. Inputs from eye-specific layers of LGN remain segregated when they enter visual cortex layer 4. Within cortex, signals from the two eyes converge within other layers (Fig. 11A). Outside layer 4, the relative strength of input from the two eyes varies in a columnar fashion, with monocular responses over the centers of ocular-dominance columns, and binocular responses at the borders between columns. (Fig. 11) iii. The information from the two eyes, looking at the same part of the visual field, is compared to produce binocular depth perception.

Figure 19. Adjacent regions of visual cortex are primarily responsive to the left or right eye (ocular dominance). (A) Eyes pecific layers in LGN project to eye-specific columns in the input layer of visual cortex, layer 4. Layer 4 cells project to other layers such that they mix with layer 4 inputs from adjacent other-eye columns. Thus, cells in column centers respond to one eye, and cells between columns respond to both eyes, with a gradation between. (B) Left and right ocular dominance regions are shown in a flattened view of visual cortex. (C) Continuous changes in orientation-selective responses are mapped across the surface of visual cortex. (D) In a cross sectional view of visual cortex, eye-specific stripes consist of a series of smaller columns with different orientation selectivity. From Purves et al., Neuroscience, 2017. Figs. 12.10, 12.11; Illustrations by M. Rosen.

3. Parallel processing in secondary and association visual cortices (Fig. 12) 1. Information received in primary visual cortex is processed, then sent to secondary visual cortex (Area 18). M and P pathways remain segregated in V2.

2. M and P channels diverge after V2

a. Motion and location information (M pathway) eventually projects to parietal cortex (dorsal pathway), particular to area MT i. In area MT, neurons are highly sensitive to location and direction of motion, but not to form. ii. Lesions of MT and other parts of this dorsal pathway diminish motion perception and smooth pursuit eye movement b. Form and color information (P pathway) eventually projects to inferotemporal cortex (ventral pathway), particularly to area V4 i. In area V4, neurons are highly selective for color and/or form, but not location ii. E.g., some neurons selective to a particular face, located anywhere in a large part of visual field iii. Lesions of V4 or other parts of the ventral pathway diminish form and color vision.

Figure 12. Dorsal (location and direction of motion) and ventral (form and color) visual pathways exiting primary visual cortex.

Adapted from Purves et al., Neuroscience, 2017, Fig. 12.16

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Review Questions: 1. Retinal ganglion cells have a center-surround receptive field. Describe it, and how light at different locations in this receptive field changes RGC firing.

2. Describe the flow of visual information from retina to the primary visual cortex 3. Visual structures on the right side of the brain, including the optic tract, lateral geniculate, and visual cortex, represent the left visual field. How does this occur?

4. What differences in retinal ganglion cells are preserved in the different layers of the lateral geniculate nucleus?

5. Explain why the representation of the upper, peripheral part of visual receptive fields is particularly sensitive to loss of blood supply by the middle cerebral artery.

6. Many visual cortical neurons are orientation-selective. What does this mean and how does it originate?

7. Describe the different visual stimulus properties processed in the dorsal and ventral pathways in cortex.Â

Vision III â&#x20AC;&#x201C; Sam Crish, PhD Lecture Objectives 1. Identify other major pathways from the retina, and relate to function, including from photosensitive ganglion cells.

2. Describe the pathways for and understand the function of reflexes related to vision.

3. Know the disorders that can result from problems with those pathways.

4. Terms: intrinsically-photosensitive retinal ganglion cell suprachiasmatic nucleus of the hypothalamus circadian rhythm superior colliculus brachium of the superior colliculus pretectum pupillary light reflex (pupillary constriction) direct light reflex consensual light reflex accommodation for near vision orienting eyes, head, neck pupillary dilation intermediolateral horn of spinal cord superior cervical ganglion

Hornerâ&#x20AC;&#x2122;s syndrome miosis ptosis scotoma anopia hemianopia quadrantanopia homonymous heteronymous macular sparing retinal detachment tumor of pituitary or hypothalamus central retinal artery anterior choroidal artery posterior cerebral artery middle cerebral artery anhidrosis Argyll-Robertson pupil

I. OTHER VISUAL PATHWAYS AND VISUAL REFLEXES A. Suprachiasmatic nucleus of hypothalamus (Fig. 1) Receives input via retino-hypothalamic tract from intrinsically-photosensitive retinal ganglion cells

Figure 1 Fiber-stained section through diencephalon, showing location of suprachiasmatic nucleus (SCN). From Dept. of Anatomy and Neurobiology archival material

i. Intrinsically-photosensitive retinal ganglion cells (ipRGC) Specialized ganglion cells that, unlike other ganglion cells, have a photopigment â&#x20AC;&#x201C; melanopsin â&#x20AC;&#x201C; that allows them to respond to light directly, i.e., without input from photoreceptors. (Figure 2A, B). They the pigment melanopsin (which absorbs light in the blue range, Figure 2C) and using a G-protein coupled phototransduction process. Their response to light is sluggish compared to rods and cones; they measure overall light intensity. Increased light levels are depolarizing, causing increased numbers of action potentials in the ganglion cell. These ganglion cells function in pupillary light reflex, circadian rhythms, and probably conscious perception. Explains why circadian rhythms persist when form vision is lost due to rod/cone degeneration.

They project to several brain targets, the main target being the suprachiasmatic nucleus Figure 2A, D)

Figure 2. Intrinsically-photosensitive retinal Ganglion Cells (ipRGCs). Large ganglion cells with extensive dendritic arbors (A, top left) Discovered in the early 2000s, these cells respond directly to light (A, right) and project to the suprachiasmatic nucleus (scn, A, bottom left). These cells are located in the retinal ganglion cell layer and receive input from bipolar cells (not shown) and amacrine cells (B). They respond to wavelengths of light, with peak response at ~500 nm (C), and project to several targets in addition to the SCN (D)

ii. Regulates circadian rhythms: alternate system to measure ambient light: B. Brachium of the superior colliculus (Fig. 3) Composed of optic nerve fibers that bypass the LGN, continuing dorsally and medially. Two targets of the brachium of the superior colliculus: 1. Pretectum a. Located in the rostro-dorsal midbrain b. Pretectum on one side receives direct input from parts of both retinas viewing contralateral visual field (input from contralateral eye crosses in optic chiasm). c. Functions in pupillary light reflexes and accommodation for near vision.

2. Superior Colliculus a. Located dorsal and slightly caudal to pretectum

b. Superior Colliculus on one side receives direct input from parts of both retinas viewing contralateral visual field (input from contralateral eye crosses in optic chiasm). c. Functions in orienting eyes, head, and neck to novel visual (and other sensory) stimuli and other spatially directed movements, like reaching.

C. Visuomotor reflexes 1. Pupillary light reflex (see Fig. 3) – CONSTRICTION of pupil, not dilation. a. The reflex: Light shone in one eye causes constriction of same pupil (direct light reflex) and constriction of pupil in contralateral eye (consensual light reflex) b. Pathway (constriction portion of path is under parasympathetic control): i. Afferent path: Retinal ganglion cells project to pretectum ii. Efferent path: Pretectum projects bilaterally to Edinger-Westphal nucleus Ciliary ganglion  • Pupillary sphincters in ipsilateral eye (direct light reflex) • Pupillary sphincters in contralateral eye (consensual light reflex)

Figure 3. Pupillary light reflex pathways. If the optic nerve is partially damaged (A), shining a light into that eye will produce a diminished direct and consensual response (left); but both will be present when the undamaged side is illuminated (right). This is termed a relative afferent pupillary defect. A total lesion at A would produce a blind eye, which would induce neither a direct nor a consensual response when illuminated. If the lesion occurs in the optic tract (B) or pretectum, neither response is lost. Although the reflexes may be weaker, this is not easily discerned clinically. However, a large lesion in the posterior (dorsal) midbrain (e.g., pinealoma) would

weaken pupillary responses bilaterally. If the lesion occurs in the oculomotor nucleus or nerve (C), both direct and consensual responses will be lost in the eye on the lesion side, but they will be present in the other eye. Adapted from Haines, Neuroanatomy, 2012, Fig. 8-34; illustrations by M. Rosen.

c. Clinical significance: Diagnostic tool for testing brainstem and cranial nerve function. d. Pupillary dilation is more complex (Fig. 4). i. Under sympathetic control ii. Includes hypothalamic projections to intermediolateral horn of spinal cord superior cervical ganglion pupillary dilator muscles in iris iii. Horner’s syndrome is a loss of sympathetic input to the eye/face characterized by: • pupillary constriction (miosis) • partial ptosis (drooping eyelid) • anhidrosis (loss of facial sweating) e. Argyll-Robertson pupil. Result of syphilis infection of CNS i. Small pupils with weak pupillary light reflex. However, visual acuity is good. Also, pupil can constrict in Accommodation to Near Vision (below), indicating intact Edinger-Westphal and ciliary ganglia. ii. Lesion appears to be in pretectum or pathway to EdingerWestphal nucleus, rather than in sensory pathway or within Edinger-Westphal nucleus.

2. Lens Accommodation: Process by which shape of the lens is actively controlled to allow the eye to focus on objects within 10-20 feet. a. Afferent path: Retinal ganglion cells LGN Visual Cortex ? b. Efferent path: Midbrain center near E-W Edinger-Westphal nucleus Ciliary ganglion Contraction of ciliary muscle Lens thickening 3. Accommodation for Near Vision: A series of motor responses required to view nearby objects. Unlike the simple pupillary light reflex (shining light constricts the pupil), this involves the visual cortex in order to determine that an object is not in focus, and to alter several elements to achieve focus. a. Stimuli include retinal disparity (mismatched images on the two retinas) and blurred retinal images (images without sharp contours) b. Cortical control of several motor responses

i. Pupillary constriction (anticipating that near object may be brighter, to let in less light) ii. Lens accommodation (to focus on near object) iii. Convergence of the eyes, via contraction of medial rectus (external eye) muscles (so both eyes point to near object)

Figure 4: Pathway for pupillary dilation.

Adapted from Haines, Neuroanatomy, 2012, Fig. 8-46.

II. CLINICAL ISSUES AFFECTING VISION 1. The eye/retina a. Glaucoma: one factor is increased fluid pressure in the eye i. Aqueous humor produced in posterior chamber, flows into anterior chamber through pupil; drains into venous circulation via meshwork at junction of iris and cornea. ii. Inadequate drainage can increase intraocular pressure. Can ultimately damage optic nerve. b. Papilledema i. â&#x20AC;&#x153;choked diskâ&#x20AC;? visible in ophthalmic inspection is result of swollen optic disc at the head of the optic nerve ii. results from high intracranial pressure, exerted through subarachnoid space to eye

iii. damage to axons of optic nerve can lead to partial or complete loss of vision in the affected eye c. Corneal imperfections (e.g., astigmatism) d. Cataracts (increased opacity of lens). UV-exposure contributes. Surgically correctable. e. Macular degeneration: loss of photoreceptors in and around fovea f. Deficits in color vision: multiple disorders resulting from the genetic lack or malformation of cone pigments. These cause perceptual disorders collectively called â&#x20AC;&#x153;color-blindnessâ&#x20AC;?. Characterized by inability to distinguish certain colors.

There are multiple types.

Most common deficits involve L (red) and M (green) cones i. Genes for L and M cones are located on X chromosome, so males are much more likely to display these deficits. Genes differ by only a few amino acids, so gene alteration can occur during chromosomal crossingover in meiosis. ~6% of men have anomalous red or green pigments; ~ 2% of men are missing red or green pigments entirely. ii. Result is reduced sensitivity to light at wavelengths corresponding to the missing photopigment, and reduced ability to distinguish colors in the green to red part of the spectrum. iii. protanopia involves photopigments in the L-cone (red). iv. deuteranopia involves photopigments in the M-cone (green). v. Deficits in S-cones with blue photopigments (tritanopia) are rare. Since they occur on an autosome (chromosome 7), they affect men and women equally.

2. Outside of the eye A. Lesions at different points along the central visual pathway display characteristic features (Fig. 5). Terms to describe visual deficits: 1. A scotoma refers to reduced or non-functional vision in a small part of the visual field, surrounded by normal vision. It typically occurs due to issues with a part of the retina.

2. Anopia means lack of vision, and is used in reference to large regions of the visual field. It refers to the part of the visual field lacking vision, e.g., left/right (sometimes contralateral/ipsilateral), and upper/lower visual field.

3. Many lesions cause deficits in the same part of the visual field viewed by both eyes, i.e., they are congruent. These deficits are termed homonymous.

Lesions that are not in the same part of the visual field for each eye are termed heteronymous.

4. Lesions may affect half of the visual field (hemianopia) or one quarter of the visual field (quadrantanopia) B. Lesions of the eye or optic nerve: partial or total blindness in one eye.

1. A variety of sources: a. Retinal detachment b. Papilledema: increased intracranial pressure can block axon transport in retinal ganglion cell axons. c. Retina supplied by the central retinal artery, entering through optic disc.

2. Retinal damage causes deficit in opposite part of visual field, because the eyeâ&#x20AC;&#x2122;s optics result in an inverted image on the retina.

C. Lesions at the optic chiasm 1. Most common are lesions of crossing fibers due to tumor of the pituitary or hypothalamus 2. Visual deficit is in the temporal visual fields on both sides. WHY? If loss is complete, termed Bitemporal Heteronymous Hemianopia.

3. Larger lesions can affect uncrossed fibers, resulting in total blindness.

4. Usually accompanied by endocrine disorders D. Lesions of the optic tract or lateral geniculate nucleus 1. There is a loss of vision in the contralateral hemifield for each eye. If total, this is termed Homonymous Hemianopia, and would be further specified for the Right or Left visual field.

2. Macular vision is not spared by total lesions of these structures.

3. Note proximity of optic tract to cerebral peduncles: possible motor Involvement 4. Optic tract may be affected by tumor, vascular, or CSF related problems. Blood supply is by anterior choroidal artery.

5. LGN lesions are rare

Figure 5. Visual field defects produced by lesions at different places in the visual pathway.

Visual fields are diagrammed as described in Figure 15. Regions of normal vision are indicated in white, regions of loss of vision are indicated in grey. Purple circles indicate potential regions of macular sparing during injury to central visual structures. Adapted from Haines, Neuroanatomy, 2012, Figure 8-50.

E. Lesions of the optic radiation 1. If total: loss of vision in the contralateral hemifield for each eye, termed Homonymous Hemianopia (specified for Right or Left visual field).

2. Because the optic radiation separates into two parts on its path to visual cortex, lesions can affect only one of these pathways. a. The more medial part passes underneath the parietal lobe and terminates in the cuneus. Posterior cerebral artery supplies this part of optic radiation.

A total loss causes Homonymous Lower Quadrantanopia (specified for Right or Left visual field). b. Meyer's loop passes through the temporal lobe, terminating in the lingual gyrus. Temporal lobe lesions principally affect fibers in Meyers loop, causing Homonymous Upper Quadrantanopia (specified for Right or Left visual field). Middle cerebral artery supplies Meyers loop.

F. Lesions of primary visual cortex 1. Total loss of visual cortex on one side results in Homonymous Hemianopia (specified for Right or Left visual field). Posterior cerebral artery supplies visual cortex.

2. Lesions restricted to the cuneus or lingual gyrus. May be due to occlusion of branches of the posterior cerebral artery. a. Cuneus: contralateral lower homonymous quadrantanopia b. Lingual gyrus: contralateral upper homonymous quadrantanopia Clinically, damage to central visual structures is often incomplete.

Thus visual field deficits are typically less complete than those depicted here (in relation to the optic chiasm, optic tract, optic radiation, or visual cortex).

Macular sparing is possible with injury to central visual structures. One theory is that some part of the macular representation is supplied by the middle cerebral artery, but this is controversial in the field. In cases of macular sparing, the deficit is described as in the examples above, but noting existence of macular sparing.

G. Lesions of pathways beyond primary visual cortex can have specific, sometimes very unusual effects.

1. Lesions of the dorsal pathway: diminish motion perception and smooth pursuit eye movement 2. Lesions of the ventral pathway: diminish form and color vision

Review Questions: 1. Describe the circuitry for lens accommodation.

2. What are the separate responses associated with accommodation for near vision?

3. Describe the circuitry for pupillary light reflex.

4. Identify the site of a lesion which causes loss of pupillary light reflex in both eyes when shining light in the left eye.

5. What disorder would result in sparing of macular vision? Identify a location where such a lesion could occur.

6. What visual field deficit results from total destruction of the lateral geniculate nucleus on one side?

7. Describe the effects on vision of blockade of a) the anterior choroidal artery, b) the middle cerebral artery, and c) the posterior cerebral artery. Use the proper terminology.

Chemical Senses Jeffrey G. Mellott, Ph.D. Learning Objectives: To identify the basic organization and functions of taste and olfaction.

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Describe the location and structure of olfactory receptor neurons.

Understand olfactory transduction.

Describe the olfactory pathways.

Understand lesions/deficits that affect olfaction.

Describe the location and structure of taste buds, taste receptor cells, and papillae Understand taste transduction.

Describe the taste pathways.

Understand lesions/deficits that affect taste.

Understand the functions of the trigeminal chemoreception system.

Outline: A. Olfaction: I. Olfactory Epithelium II. Olfactory Receptors III. Olfactory Transduction IV. Central Olfactory Pathways a. Olfactory bulb i. Mitral cells ii. Tufted cells b. Olfactory tract c. Anterior olfactory nucleus d. Olfactory tubercle e. Pyriform cortex f. Amygdala g. Entorhinal cortex V. Clinical a. Anosmia b. Hyposmia B. Taste I. Organization of peripheral system II. Taste Buds III. Taste Receptors a. Structure b. Distribution IV. Taste Transduction V. Basic Tastes a. Sweet

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b. Sour c. Salty d. Bitter e. Umami VI. Taste Pathways VII. Clinical a. Ageusia b. Hypogeusia c. Dysgeusia C. Trigeminal (chemosensory irritant)

Overview From an evolutionary perspective, the chemical senses are thought of as the oldest or most primitive sensory systems. There are three chemical sensory systems associated with the nose and mouth: (1) the olfactory (smell), (2) gustatory (taste) and (3) trigeminal (chemosensory irritant) systems. Each of these systems detects chemicals in the environment. The olfactory system detects airborne molecules, called odorants. Olfactory information influences social interactions, reproduction, defensive responses and feeding behavior. The gustatory system detects ingested tastants, which are primarily water or fat-soluble molecules. Tastants provide information about quality, quantity and safety of ingested food. The trigeminal system provides information about irritating or noxious molecules that come into contact with the skin and mucous membranes of the eyes, nose or mouth. All three chemosensory systems use receptors that interact with relevant molecules in the environment. For taste and smell, sensory transduction relies primarily on G-protein coupled receptors and second messenger-mediated signaling.

Clinical Significance Assessment of taste, when carried out, is usually done more for testing of the cranial nerves than for specific interest in the gustatory system itself. Loss of taste is often accompanied by more significant neurological deficits. Loss of smell, however, can occur in the absence of other deficits. A decrease in ability to smell is a common feature of aging. Whether a consequence of normal aging or a result of trauma, loss of smell and loss of taste can lead to decreased appetite. Loss of smell or taste can become a significant issue in patients who are compromised nutritionally.

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A. Olfaction Olfactory epithelium Olfactory epithelium with major cell types. Bowmanâ&#x20AC;&#x2122;s glands produce mucus. Olfactory cells are generated continuously from dividing stem cells.

Figure 15.7

Olfactory Receptors Olfactory receptor cells are located in the olfactory epithelium in the nasal cavity (see figure; 15.1). The receptor cells are neurons that, like other primary sensory neurons, have a peripheral and a central process. The central processes of the receptors together make up the olfactory â&#x20AC;&#x153;nerveâ&#x20AC;?, although a single nerve is never formed. Rather, the nerve consists of many separate fascicles that penetrate the adjacent cribriform plate of the ethmoid bone and then immediately enter the olfactory bulb.

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Olfactory transduction The peripheral process of an olfactory receptor cell is short, extending from the cell body to the surface of the olfactory epithelium, where it gives rise to cilia. The cilia are bathed in a layer of aqueous mucus that is produced by Bowmanâ&#x20AC;&#x2122;s glands and the supporting cells. Odor molecules must dissolve in the mucus layer and diffuse to receptors on the microvilli. Hydrophilic (watersoluble) molecules can dissolve and diffuse in the mucus directly. Hydrophobic molecules do not easily dissolve in the mucus. The mucus contains a large number of odorant-binding proteins that can transport hydrophobic molecules through the mucus layer. The odorant molecule can then bind with receptors on the olfactory receptor cell cilia and set up a signal that is conducted to the brain by the central process of the olfactory receptor cells.

Applying odorants to the cilia evokes a slow receptor potential. The receptor potential propagates down the dendrite to the soma of the olfactory receptor cell. Action potentials are first evoked at the axon initial segment (and recorded in the soma). These action potentials then propagate down the axon of the receptor cell. Generation of receptor potentials in response to odors takes place in the cilia of receptor neurons.

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Odorants evoke large depolarizations (inward currents) when applied to the cilia (above; left panel; 15.8) but only small currents when applied to the cell body (above; right panel; 15.8).

One receptor type/one gene/one protein/one odorant type Signal transduction in the olfactory system occurs via approximately 1000 distinct olfactory receptor molecules. Each receptor cell expresses only one receptor molecule type. The structure of each receptor gene is unique, so that each receptor type expresses a unique protein. This allows each receptor type (protein) to bind a different odorant. (i.e. each olfactory receptor cell seems to express just one â&#x20AC;&#x201C; or only a very few â&#x20AC;&#x201C; of the 1000 types of receptor genes).

Thus, there are 1000 types of receptor cells each identified by the particular receptor gene that it expresses.

The olfactory epithelium is organized into a few large zones. Each zone contains receptor cells that express a unique subset of receptor genes. Three different groups of genes are mapped in this figure. Each group has a different zone of distribution and does not overlap with any other group. Within each zone of receptor sub-type, individual receptor cells are scattered randomly.

In the figure below, each receptor cell with a unique receptor protein is color coded.

If you were to record the pattern of firing in different receptor cells caused by exposure to the same odor molecule, you would get different responses. For example, the citrus odor causes strong firing in the green receptor cell type, weak firing in the blue cell and no firing in the red cell. The almond odor causes no firing in the green receptor, very weak firing in the blue receptor and strong firing in the red receptor. If you look at the combination of firing patterns in each of the three receptor types to the four different odors tested, it looks as though the green receptor cell is selective mainly to citrus, less strongly to peppermint and least selective to the almond and floral odors. Note: since a single receptor subtype can respond to more than one odor (although not many more) there is some ambiguity in telling odors apart at the level of the receptor cells. (Neuroscience: Exploring the Brain. 3rd ed: Bear et al)

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Olfactory signals are transduced through G-protein coupled receptors. Each olfactory receptor type is linked to a G protein-coupled receptor. Binding of an odorant molecule to the receptor causes the activation of a G-protein coupled receptor. This interaction causes the release of the G-proteinâ&#x20AC;&#x2122;s GTP-coupled a-subunit, Golf, which stimulates adenylyl cyclase to produce cAMP. Increased cAMP levels cause the opening of cyclic-nucleotide gated cation channels, which causes membrane depolarization and action potentials in the sensory axon, and transmission of signals to the olfactory bulb.

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CENTRAL OLFACTORY PATHWAYS The Olfactory Bulb As the axons leave the olfactory epithelium, they coalesce to form the olfactory nerve (Cranial nerve I). Each olfactory nerve projects ipsilaterally to the olfactory bulb, which lies on the ventral aspect of the cerebral hemisphere. The most distinctive feature of the olfactory bulb is an array of more or less spherical accumulations of neuropil 100-200 Âľm in diameter, called glomeruli, which lie just beneath the surface of the bulb and are the synaptic target of the primary olfactory axons.

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Olfactory receptor cell axons synapse with mitral cell apical dendritic tufts, tufted cells and periglomerular cell processes within glomeruli. Granule cells and mitral cell lateral dendrites constitute the major synaptic elements of the external plexiform layer.

Within each glomerulus, the dendrites of periglomerular cells form inhibitory synapses with mitral cell dendrites (these are dendro-dendritic synapses). The secondary dendrites of mitral and tufted cells form excitatory synapses on the dendrites of granule cell interneurons. The granule cells make inhibitory synapses on other dendrites. This forms a “curtain of inhibition” that must be overcome by a strong enough excitation caused by an odorant binding to a receptor cell. And since only strong responses to odorants at the receptor level can overcome this inhibition curtain, odorant responses are recorded at the level of the glomerulus as excitatory “peaks”. These discrete peaks of excitation that stand out from the surrounding inhibition are what confer odorant-selectivity to the responses.

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The figure above (15.1) shows the central olfactory pathways. Olfactory information diverges quickly to reach multiple areas in the forebrain. Many of these targets are components of the limbic system. This close association between the olfactory and limbic systems underlies the many and varied effects an odor can elicit, from the “adrenaline jolt” that can accompany the smell of smoke to the long-ago memory of grandma’s kitchen that comes forth with the smell of cookies baking.

Axons from mitral and tufted cells form the lateral olfactory tract. Lateral olfactory tract fibers terminate in the olfactory cortex which is a broadly defined area on the ventral surface of the telencephalon. Areas that are part of the olfactory cortex are: anterior olfactory nucleus, olfactory tubercle, piriform cortex, anterior cortical amygdaloid nucleus, peri-amygdaloid nucleus and lateral entorhinal cortex. Lateral olfactory tract axons caudally form lateral olfactory stria which terminate in the olfactory tubercle and piriform cortex. Posterior portion of the lateral olfactory tract terminates in amygdala and entorhinal cortex.

Olfactory information is processed in several regions of the cortex. Information from the olfactory bulb is transmitted by the mitral and tufted relay cells, whose axons travel in the lateral olfactory tract.

Tufted cells project mainly to the anterior olfactory nucleus and the olfactory tubercle.

Mitral cells project to five different regions of the olfactory cortex: (1) the anterior olfactory nucleus which innervates the contralateral olfactory bulb (2) the olfactory tubercle (3) the piriform cortex (4) parts of the amygdala (5) parts of the entorhinal cortex

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Olfactory pathways as seen from the inferior surface of the brain.

The conscious discrimination of odors most likely occurs in the orbitofrontal and frontal cortices (neocortex region). These two regions receive olfactory information via two separate projections â&#x20AC;&#x201C; one through the thalamus and one directly to the neocortex.

Emotive aspects of olfactory sensation arise from the limbic projections which involve the amygdala and hypothalamus.

The olfactory tubercle is involved in multisensory processing and reward behavior/cognition.

The entorhinal cortex is involved in olfactory memories.

(Note: While many mammals have a vomeronasal system that mediates pheromone-induced signaling, there is insufficient evidence that such a system is functionally present in humans).

To summarize, what makes the olfactory system unique?

Two features of olfactory receptors make the olfactory system unique among the sensory systems. First, the olfactory system is the only one in which the first synapse occurs in the telencephalon (this is because the olfactory bulb is part of the telencephalon). Second, each of the approximately 100 million olfactory receptor cells are replaced about every two months. The olfactory receptors, which are neurons, are constantly dying and being replaced by new cells which are derived from the basal cells). (Taste receptors also turn over, but they are not neurons).

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Clinical notes.

Anosmia: total loss of the sense of smell.

Hyposmia: reduced sense of smell Anosmia can result from numerous things, including blockage of the airways, infection, or a tumor affecting the olfactory tract or bulb. The fibers of the olfactory nerve can be broken as a result of head trauma; a car accident, for example, can force the brain forward and shear off the olfactory nerve fibers as they leave the cribriform plate.

Olfactory hallucinations can also occur, most often as a result of an epileptic seizure that involves the anterior medial temporal lobe (where the pyriform and entorhinal cortices are located).

Olfaction makes an important contribution to taste. Olfactory changes can also contribute to lessened food intake and nutritional issues.

B. Taste Organization of the Peripheral Taste System •

Approximately 4000 taste buds in humans are distributed throughout the oral cavity and upper alimentary canal. Each taste bud contains 30 to 100 taste cells (the sensory receptor cells), plus a few basal cells. Taste buds are located on the tongue, palate, pharynx and, in smaller numbers, on the epiglottis and upper third of the esophagus.

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On the tongue, most taste occur in small elevations called papillae. There are three types of papillae: fungiform (which contain about 25% of the total number of taste buds), circumvallate (which contain 50% of the taste buds), and foliate (which contain 25%).

Fungiform papillae are found only on the anterior two-thirds of the tongue; the highest density is at the tip. They have a mushroom-like structure (hence their name) and typically have about 3 taste buds at their apical surface. There are 9 circumvallate papillae arranged in a chevron at the rear of the tongue. Each consists of a circular trench containing about 250 taste buds along the trench walls. Two foliate papillae are present on the posterolateral tongue, each having about 20 parallel ridges with about 600 taste buds in their walls.

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Thus, chemical stimuli on the tongue first stimulate receptors in the fungiform papillae and then in the foliate and circumvallate papillae. Tastants subsequently stimulate scattered taste buds in the pharynx, larynx, and upper esophagus.

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Taste cells in individual taste buds synapse with primary afferent axons from branches of three cranial nerves: the facial (VII), glossopharyngeal (IX), and vagus (X) nerves. The taste cells in fungiform papillae on the anterior tongue are innervated exclusively by the chorda tympani branch of the facial nerve; in circumvallate papillae, the taste cells are innervated

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exclusively by the lingual branch of the glossopharyngeal nerve; and in the palate they are innervated by the greater superior petrosal branch of the facial nerve. Taste buds of the epiglottis and esophagus are innervated by the superior laryngeal branch of the vagus nerve. â&#x20AC;˘

The initiating events of chemosensory transduction occur in the taste cells, which have receptors on microvilli that emerge from the apical surface of the taste cell. The synapses that relay the receptor activity are made onto the afferent axons of the various cranial nerves at the basal surface. The apical surfaces of individual taste cells in taste buds are clustered in a small opening (about 1 mm) near the surface of the tongue called a taste pore. Taste cells have a lifetime of only about 2 weeks and are normally regenerated from basal cells.

Taste Buds

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Taste receptors Taste receptors are present on special receptor cells. These cells are non-neuronal. Numerous receptor cells are grouped with other cell types (support cells and basal cells) into taste buds.

Taste receptor cells have an apical region with microvilli that contain the transduction apparatus. The microvilli are bathed in saliva, so only substances that dissolve in saliva can activate the taste cells.

Taste Transduction Taste cells are polarized epithelial cells with an apical and basal domain separated by tight junctions. Tastant-transducing channels (salt and sour) and G-protein-coupled receptors (sweet, amino acid, bitter) are limited to the apical domain. Intracellular signaling components that are coupled to taste receptor molecules are also enriched in the apical domain. Voltageregulated Na, K, and Ca channels mediate neurotransmitter release from presynaptic specializations at the base of the cell onto terminals of peripheral sensory afferents. These channels are limited to the basolateral domain. The neurotransmitter, serotonin, among others, is found in taste cells, and serotonin receptors are found on the sensory afferents. TRP (transient receptor potential) channels, which facilitate G-protein coupled receptor-mediated depolarization, are expressed in taste cells.

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There are five basic tastes: 1.sweet 2.sour 3.salty 4.bitter 5.umami (the taste associated with monosodium glutamate).

There are specific receptor mechanisms to deal with each type.

Molecular mechanisms of taste transduction via ion channels and G-protein coupled receptors.

(A) Cation selectivity of the amiloride-sensitive Na+ versus H+ sensitive proton channel provides the basis for specificity of salty tastes. (B) Sour tastants are transduced by a proton-permeant, non-selective cation channel that is a member of the TRP channel family. In both cases, positive current via the cation channel leads to depolarization of the cell. (C-E) For sweet, amino acid (umami) and bitter tastants, different classes of Gprotein coupled receptors mediate taste transduction. (D) For amino acid (umami) tastants, transduction occurs via a PLC-mediated IP3-dependent mechanism that leads to Ca++ entry. (E) For bitter tastants, a distinct set of G-proteins, the gustducins, are involved in the transduction process. Gustducin is not found in 14 sweet or amino acid receptor-expressing taste cells.

Overlapping distribution of taste /taste cells on tongue Sweet, umami, salty: tip of tongue.

Behaviors activated: mouth movements, salivary secretion, insulin release, swallowing.

Sour and bitter: lowest at tongue tip. Greatest on back and sides.

Behavior elicited: grimaces, puckering, high salivary secretion to dilute tastant.

Each taste elicits focal activity in the taste cortex. Thus, from the taste receptors, which are different for each taste, to the cortex where taste processing localized to different regions, tastes are segregated throughout the taste system.

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TASTE PATHWAYS Taste receptor cells are innervated by cranial nerves VII, IX and X. The chorda tympani branch of the facial nerve responds best to NaCl and sucrose (that is, for a given concentration a greater number of action potentials and axons are activated by these substances); the glossopharyngeal nerve responds best to acid and quinine; and the superior laryngeal branch of the vagus nerve responds best to acid and water. These observations imply that a single peripheral neuron might respond best to sucrose, for example, but could also be activated by fructose, NaCl, and acetic acid. The information contained in the patterns of action potentials elicited by each of these tastants arises from the activation of the several taste cells that synapse with the primary afferent neurons. This peripheral convergence has the effect of increasing the sensitivity of the taste system to a given stimulus.

PERIPHERAL TASTE PATHWAYS

N. VII – Facial – anterior tongue - Geniculate ganglion.

N.IX – Glossopharyngeal – lateral posterior tongue - petrosal ganglion N.X – vagus – pharynx – nodose ganglion.

Solitary nucleus – main visceral nucleus in brainstem. Two regions: rostral gustatory nucleus caudal cardiorespiratory nucleus. Taste fibers (nerves X, IX, VII) terminate in rostral solitary nucleus. Termination is topographic along the rostral-caudal axis of the rostral portion of the nucleus of the solitary tract (also called gustatory nucleus). Facial nerve terminates rostrally, glossopharyngeal nerve in the mid region and vagus nerve caudally. This topographic arrangement allows for integration of information from visceral and taste systems.

The caudal part of n. solitarius receives innervation from sub-diaphragmatic branches of the vagus, which control gastric motility.

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CENTRAL TASTE PATHWAYS The central processes of the taste fibers terminate in the rostral portion of the solitary nucleus (nucleus of the solitary tract; nucleus tractus solitarius). The rostral part of the solitary nucleus is sometimes called the gustatory nucleus. The gustatory nucleus gives rise to the central taste pathways. The gustatory nucleus projects to the ipsilateral thalamus: the taste pathway remains ipsilateral from tongue to cortex. The ascending taste fibers from the gustatory nucleus travel in the central tegmental tract.

Within the thalamus, taste information is processed in a subdivision of the ventral posterior medial nucleus distinguished by small cells. This taste subdivision is therefore called the parvicellular part of the VPM (VPMpc. “Parvicellular” means “small-cell”). The remainder of the VPM takes care of the remaining general sensory information from the head (primarily from the trigeminal system). The primary taste area in cortex is located near the representation of the tongue in somatosensory cortex (which is represented in the inferior somatosensory cortex in the postcentral gyrus) and extends into the frontal operculum and the anterior insula.

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â&#x20AC;&#x153;Higher orderâ&#x20AC;? cortical areas are located in orbitofrontal cortex that integrate gustatory, olfactory, visual and somatosensory inputs to give rise to the appreciation of flavor and food reward. Some of this information ultimately reaches the hypothalamus and the amygdala (both of which help control feeding behavior).

Main taste pathway Axons from rostral (gustatory) part of the solitary nucleus project to ventral posterior complex of the thalamus, where they terminate in the medial half of the ventral posterior medial nucleus.

From here projections go to regions of neocortex including anterior insula in the temporal lobe (insular taste cortex) and the operculum of the frontal lobe. The pathway from solitary nucleus to ventral posteromedial nucleus to cortex â&#x20AC;&#x201C; underlies discriminative aspects of taste, and is exclusively ipsilateral (unlike other sensory systems).

Secondary taste pathway Neocortical area: caudolateral oribitofrontal cortex. This region acts as an integration site for taste, visual and olfactory cues that are associated with the ingestion of food.

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Reciprocal connections Between solitary tract nucleus, via the pons, to the hypothalamus and amygdala. These projections influence affective aspects of food.

Clinical Notes Ageusia: complete loss of taste (rare).

Hypogeusia: reduced taste (lesions that affect peripheral or central pathways (e.g., Bell’s palsy; lateral medullary syndrome).

Dysgeusia (parageusia): distortion of taste (result of medication).

C. Trigeminal Specialized component of the pain and temperature-sensing somatosensory pathways in the head and neck. The trigeminal system makes an important contribution to what we call “taste”.

Polymodal nociceptive receptor neurons activated by high concentrations of irritating chemicals that are in direct contact with mucous membranes of head – mouth, nose, eyes.

Ammonia (smelling salts), ethanol (liquor), acetic acid (vinegar), CO2 (in soft drinks), and capsaicin (chili peppers).

This “pain” information is relayed to cerebral cortex along with other trigeminal pain and temperature information (i.e., via spinal V tract and nucleus, ventral trigeminothalamic tract, etc.).

While these chemoreceptors are critical to detect harmful stimuli, they are also of great use to motivate one to eat food if the olfactory nerve and/or taste buds are compromised. For a patient who is older and sick, using spicy food is sometimes a way to introduce nutrients.

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Self-Test Questions 1) Below are some components of olfactory transduction: What is the order of activation?

A) Golf G-protein B) Odorant binds to receptor C) Calcium-activated chloride channel D) cAMP-gated ion channel E) Adenylyl cyclase III 2) The sour transduction system involves: A) Heterodimeric G-proteinâ&#x20AC;&#x201C;coupled receptors.

B) Depolarization due to protons entering the taste cells.

C) activation of phospholipase C. D) Activation of T1R2 channels.

E) Gustducin 3) A lesion to the chorda tympani would most likely disrupt taste transduction from: A) The epiglottis B) The posterior tongue.

C) Fungiform papillae.

D) Foliate papillae.

E) Nociceptive neurons in C.N.V.

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Winters Vestibular and Auditory Systems

VESTIBULAR AND AUDITORY SYSTEMS Bradley Winters, Ph.D.

OBJECTIVES FOR THE VESTIBULAR AND AUDITORY LECTURES 1.

Be able to explain the basic mechanism of sensory transduction by hair cells of the inner ear.

2.

Be able to distinguish the two main types of vestibular receptor organs and describe their structures. Identify the functional properties of each type of receptor organ.

3.

Describe the structure and function of the major vestibular pathways, including the vestibulo-spinal and vestibulo-ocular reflex pathways and the ascending pathway to cerebral cortex. For the reflex pathways: What vestibular receptor organs are involved, what are the central pathways, what muscle groups are the targets of these pathways, and what is the effect of activating these reflexes?

4.

Be able to explain nystagmus, both as a normal physiological response and as an indicator of a pathological condition.

5.

Be able to describe the direct connections with the cerebellum and how they contribute to vestibular function and maintenance of posture.

6.

Identify auditory functions of the outer ear and middle ear.

7.

Describe how the cochlea functions in the transduction of sound energy and in the analysis of sound frequency.

Describe the motion of the basilar membrane in response to a sound stimulus (i.e., the Traveling Wave).

Explain steps by which the motion of the basilar membrane is transformed into action potentials in auditory nerve fibers.

What mechanical properties of the basilar membrane enable different parts to response best to different frequencies of sound?

How does the sensitivity to sound frequency change along the length of the basilar membrane?

Understand different functional roles of inner and outer hair cells.

8.

Understand the flow of information within central auditory pathways.

Know the components of the pathway (fiber bundles and nuclei) from the VIIIth nerve to the auditory cortex.

Identify special functional roles of the superior olivary nucleus, the inferior colliculus, the medial geniculate body, and the auditory cortex.

Describe the anatomical basis for the representation of the contralateral sound field that occurs in auditory structures of the midbrain, thalamus, and cortex.

Be able to state the effects of lesions in major nuclei and fiber bundles within the pathway to distinguish between lesions causing deafness in one ear and those causing impairment in the response to sounds in the contralateral sound field.

Understand the principle of tonotopic organization in the central auditory pathway. Identify the tonotopic organization of the cochlea and auditory cortex.

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10.

Be able to describe the difference between conduction deafness and sensorineural deafness. Be familiar with basic audiological tests and their use in evaluating auditory dysfunction.

Suggested Readings Purves, Chapter 14 (Vestibular System) and Chapter 13 (Auditory System)

I. INTRODUCTION A.

B.

Jointly consider the two sensory systems of the VIIIth cranial nerve.

1.

Peripheral components of these systems are in close proximity, and share many anatomical and physiological features.

2.

Pathologies in periphery can affect both systems. Proper diagnosis can depend upon examination of function in both systems.

General overview 1.

Vestibular system: Designed to sense and analyze orientation with respect to gravity, linear acceleration, and angular acceleration (associated with head turning).

2.

Auditory system: Designed to sense and analyze sound.

3.

We first consider the gross structures of the ear, then the functions of the sensors and central components of each system. Some pathologies are described which illuminate the normal function of these systems.

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II.

THE EAR: GENERAL STRUCTURAL FEATURES (see Fig. 1) A.

External ear: Pinna and associated structures, external auditory meatus, tympanic membrane. Function is auditory in nature.

B.

Middle ear: Ossicular chain, middle ear muscles, round window and oval window.

Function is auditory in nature.

Figure 1. Different components of the ear. From Felten and Jozefowicz, Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, 2003, Fig. III.11.

C.

Inner ear: Includes vestibular and auditory functions. (Fig. 2) 1.

A system of bony tubes (the bony labyrinth) and, within it, membranous tubes (the membranous labyrinth) encased in temporal bone. Fluids within these tubes are essential for proper function: a.

Perilymph is located just inside bony labyrinth. It is similar in composition to cerebrospinal fluid (high sodium). b.

Endolymph is located within the membranous labyrinth. i. similar in composition to intracellular fluid (high potassium) ii. created by specialized epithelial cells iii. drains into venous sinuses through endolymphatic sac

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Figure 2. The inner ear is divided into bony and membranous labyrinths. The bony labyrinth (in white) is bounded by the petrous portion of the temporal bone (in tan). Lying within the bony labyrinth is a membrane-bound membranous labyrinth (in blue) that contains organs of hearing (the cochlear duct) and equilibrium (the utricle, saccule, and semicircular ducts). The space between bone and membrane is filled with perilymph, while the membranous labyrinth is filled with endolymph.

Sensory cells in the utricle, saccule, and the ampullae of the semicircular ducts respond to motion of the head. From Felten and Jozefowicz, Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, 2003, Fig. III.12.

2.

Receptor organs a.

Vestibular apparatus: Two chambers and three semicircular canals contain sensory receptor organs. These include the hair cells (receptor cells) and associated support structures. b.

Hearing apparatus (the cochlea): Coiled structure contains receptor organ. Like the vestibular receptor organ, the sensory cell is the hair cell.

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3.

Vestibulo-cochlear (VIIIth) nerve (Fig. 3) a.

Hair cells synapse upon vestibular nerve fibers (with cell bodies in the Vestibular or Scarpaâ&#x20AC;&#x2122;s ganglion), or on auditory nerve fibers with cell bodies in Spiral ganglion. These two nerves combine to form the VIIIth cranial nerve and pass through the skull at the internal auditory meatus.

Figure 3. Path of the vestibulocochlear (VIIIth) nerve, from origin in the inner ear, through internal auditory meatus, to termination in nuclei of the medulla. Adapted from Felten and Jozefowicz, Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, 2003, Fig. II.70.

III.

FUNCTIONAL PROPERTIES OF THE EAR: POSITION AND MOTION SENSE A.

There are two main types of receptor organs in the vestibular system.

1.

Otolith organs (utricle and saccule) serve static balance, linear acceleration.

2.

Semicircular canals (three) sense head rotation in different planes.

3.

Both systems use a mechanoreceptor called the hair cell.

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B.

Hair cell function illustrated in the utricle 1.

Organization of utricle (see Figs. 1-3) a. b. c.

Large chamber at the confluence of the three semicircular canals.

Receptor surface is called the macula; composed of hair cells, support cells, and nerve fibers. (Fig. 4A) Sitting on top of hair cells is the otolithic membrane, a gelatinous mass with calcium carbonate crystals.

Figure 4A. The macula of the utricle is organized structurally to detect tilt of the head in any direction. The mechanoreceptive sensory cells are called hair cells. Their bundles of stereocilia extend into the otolithic membrane. This membrane is a gelatinous material into which calcium carbonate crystals (otoconia) are embedded. Nerve fibers from the VIIIth nerve make contact with hair cells. (Adapted from Iurato, 1967.) Taken from Purves et al., Neuroscience 6e, 2018, Fig. 14.4.

2.

Structure of hair cell (Fig. 4B) a. b. c. d. e.

Each has 40-70 stereocilia and one larger kinocilium.

Stereocilia differ in length; there is a gradation from short to long in the direction of the kinocilium.

Adjacent hair cells are bound by tight junctions.

Hair cells have synaptic vesicles.

“Tip links” connect adjacent stereocilia, related to ion channels

Figure 4B. Left: Structure of a macular hair cell. From Felten and Jozefowicz, Netter’s Atlas of Human Neuroscience, 2003, Fig. III.17. Middle: Scanning EM of macular hair cell showing different axes of movement. From Purves et al., Neuroscience 6e, 2018, Fig. 13.10.

Right: Functional elements of hair cell, with transduction channels on tips of stereocilia and synaptic vesicles. From Purves et al., Neuroscience 6e, 2018, Fig. 13.9.

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3.

Mechanism of transduction (Fig. 5) a. b. c.

d.

The â&#x20AC;&#x153;restingâ&#x20AC;? state is characterized by inward K+ leakage, outward pumping of K+, and some release of transmitter.

Hair cells activated by the deflection, or movement, of the hair bundle Deflection in direction of kinocilium causes depolarization. i.

Deflection of hair bundle toward kinocilium opens channels located near the tips of the stereocilia. ii.

This allows K+ to enter and depolarize hair cell. Causes inward Ca++ flux, resulting in release of excitatory transmitter from hair cell, onto dendrites of primary vestibular neuron. iii.

Deflection of hair bundle away from kinocilium hyperpolarizes hair cell because it reduces number of open channels below resting level. As a result transmitter release is reduced below resting level. iv.

No effect on channel opening when deflection is at right angles to preferred direction.

This is basic mechanism of transduction by hair cells in vestibular and auditory systems (with some differences in auditory system).

Figure 5. The firing of vestibular nerve fibers depends on the direction in which the hairs are deflected.

Deflection toward the kinocilium causes hair cells to depolarize and produces an increased rate of firing in the afferent fibers. Deflection away from the kinocilium causes the hair cells to hyperpolarize and produces a decreased rate of firing in the afferent fibers. Adapted from Squire et al., Fundamental Neuroscience, 2008, Fig.

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4.

Otolith function a.

Hair cells in the utricle are arranged in a horizontal plane within the macula, but orientation and directional sensitivity differs (Fig. 6). The utricular macula thus converts head tilt or linear acceleration into selective activation of some of these hair cells.

(Fig. 7) b.

Functional role: Utricle senses linear acceleration and position with respect to gravity. c.

Saccule is arranged roughly vertically. It also analyzes head tilt and linear acceleration (Fig. 6).

Figure 6.

Arrangement of utricle and saccule within inner ear and orientation of hair cell sensitivity relative to the striola. From Purves et al., Neuroscience 6e, 2018, Fig. 14.4.

Figure 7. Both head tilt and linear acceleration result in displacement of the otolithic membrane and movement of stereocilia of hair cells.

From Purves et al., Neuroscience 6e, 2018, Fig. 14-5.

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B.

Semicircular canals 1.

Functional arrangement: Designed to sense angular acceleration that accompanies rotation of the head (Fig. 8).

Figure 8. A. Arrangement of ampulla within a semicircular canal.

B. Orientation of resting ampulla.

C. Angular acceleration causes endolymphatic flow, which in turn causes movement of cupula. Adapted from Purves et al., Neuroscience 6e, 2018, Figs. 14.7 and 14.8.

2.

The sensory organ, or ampullary crest, consists of hair cells (and support cells) that project into the ampulla, or swelling of each canal (Fig. 7). Hair cells are embedded in a gelatinous mass called the cupula. When the head undergoes rotational acceleration in the plane of the canal, the relative motion of the endolymphatic fluid against the cupula causes a deflection of the stereocilia bundle that either depolarizes or hyperpolarizes the hair cell. a.

Within the ampullary crest of a given canal, all hair cells are aligned in the same direction, so all are similarly excited by motion of the endolymph in a particular direction.

b.

Each semicircular canal is only affected by head movement only within the plane of that canal.

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Winters Vestibular and Auditory Systems

c.

Semicircular canals on the two sides of the head form functional pairs (see Figs. 9). When movement causes hair cell in one canal to be depolarized, hair cells in the other canal in the pair are hyperpolarized. The functional pairs are: i. left and right horizontal canals ii. left anterior and right posterior canals iii. right anterior and left posterior canals

Figure 9. Orientation and function of the semicircular canals in the head. A. The horizontal canals on both sides lie in the same plane and therefore are functional pairs. B. The anterior duct on one side and the posterior duct on the opposite side lie in the same plane and are therefore functional pairs. C. Superior view of the horizontal semicircular canals illustrates how the paired canals work together to signal head movement. From Purves et al., Neuroscience 6e, 2018, Fig. 14-8 and Ch 14 Clinical applications.

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IV.

VESTIBULAR SYSTEM AND REFLEXES A.

Cell bodies of vestibular nerve located in Vestibular (Scarpa's) Ganglion (Fig. 3, 10).

B.

Vestibular nuclei: Four nuclei on each side receive input from vestibular sense organs and other brain regions. They differ somewhat in inputs, outputs, and functional roles.

1.

Inputs. All nuclei receive inputs, to varying degrees, from: a. vestibular organs (semicircular canals and otolith organs) b. contralateral vestibular nuclei c. fastigial nucleus and floccular-nodular lobe of cerebellar cortex d. proprioceptive information from neck and postural muscles 2.

Outputs. In additional to reciprocal connections with vestibulo-cerebellum and contralateral vestibular nuclei, outputs include: a. spinal cord b. oculomotor nuclei c. reticular formation d. ascending projections to thalamus

3.

There is direct input from vestibular nerve to nodulus and fastigial nucleus of cerebellum (via juxta-restiform body).

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C.

Vestibular reflex pathways: control of posture, head and eye position.

1.

Vestibulo-spinal pathways (Fig. 10)

Figure 10. Inputs to vestibular nuclei and vestibulo-spinal pathways. From Felten and Jozefowicz, Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, 2003, Fig. III.18.

a.

Lateral vestibulo-spinal pathway i.

Mediates lateral vestibulo-spinal reflex: head/body tilt or linear acceleration in any direction activates antigravity muscles to counteract the tilt or acceleration ii.

Functional Role: To maintain posture and an upright position (with respect to gravity). ii.

Anatomical Pathways: - Lateral and inferior vestibular nuclei receive primary afferent input from maculae of utricle and saccule, also input from cerebellum and spinal cord.

- Axons of the lateral and inferior vestibular nuclei descend in the lateral vestibulo-spinal tract, and terminate ipsilaterally within the anterior horn of the spinal cord, at cervical through lumbar segments.

- Axons contact (directly and via spinal interneurons) alpha and gamma motorneurons to antigravity muscles (mainly axial and extensor musculature).

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Winters Vestibular and Auditory Systems

iv. b.

2.

Net effect is to increase tone in axial and extensor musculature.

Medial vestibulo-spinal pathway i.

Mediates vestibulo-colic reflex: rotation of body activates neck musculature to turn head in direction opposite the rotation of the body. ii.

Functional Role: To maintain a consistent position of the head in space during movement of the body iii.

Anatomical pathways: - Semicircular canals provide input to the medial vestibular nucleus.

- Output fibers of MVN descend in medial longitudinal fasciculus (mlf) to cervical levels, mostly ipsilateral, providing excitatory and inhibitory input to motorneurons of the neck muscles. iv.

Net effect is to stimulate appropriate neck musculature to turn head in direction opposite the rotation of the body (and to inhibit opposing muscles of the neck).

Vestibulo-ocular reflex pathways (Fig. 11) a.

Vestibulo-ocular reflex (VOR): head movement in any direction results in eye movements that are equal in angular rate but opposite in the direction of the head movement. b.

Functional Role: The function of the VOR is to stabilize the direction of gaze during movement of the head or body. c.

How it works (use example of head turning to the right: i.

Head turns to subjectâ&#x20AC;&#x2122;s right. ii.

Fluid motion in right horizontal canal causes deflection of hair cell stereocilia to depolarize them (fluid motion in left horizontal canal hyperpolarizes its hair cells). iii.

Vestibular nerve fibers on right side increase activity. iv.

Increased activity in right vestibular nuclei. v.

Activation of motorneurons controlling left lateral rectus and right medial rectus. vi.

Eyes move to subjectâ&#x20AC;&#x2122;s left, at an angular rate equal to head movement. d.

Anatomical pathways (Fig. 11): i.

Hair cells of ampullary crests of semicircular canals provide input to the medial (MVN) and superior vestibular (SVN) nuclei. ii.

Output fibers of MVN and SVN project to oculomotor nuclei (III, IV, VI) via mlf. These nuclei then project to extraocular muscles controlling eye movement. Otolith organs and lateral vestibular nucleus are involved, but to a lesser extent.

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Figure 11. Basic elements of the horizontal vestibularocular reflex. The reflex shown here is activated by a head turn to subject’s right that causes fluid movement in the horizontal canals. The response is a movement of the eyes to the subject’s left.

The reflex depends on the integrity of the medial longitudinal fasciculus (mlf): Fibers in mlf coordinate action of lateral rectus muscle (n. VI) and medial rectus muscle (n. III. Damage to mlf (e.g., multiple sclerosis) results in disconjugate movements of left and right eyes (internuclear opthalmoplegia). Adapted from From Felten and Jozefowicz, Netter’s Atlas of Human Neuroscience, 2003, Fig. III.19.

e.

Functional notes: i.

The reflex consists of movement of the eyes opposite to the direction of head rotation. ii.

They occur with head turning in all directions and involve the functions of all three sets of semicircular canals. iii.

This reflex is designed to maintain stability of the visual field. iv.

VOR circuitry can adapt to changes in vestibular input. v.

The reflex depends on integrity of vestibular nuclei, flocculonodular lobe of cerebellum, and mlf. vi.

Can be overridden by higher centers.

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3.

Nystagmus a.

Normal physiological nystagmus is an alternating slow movement of the eyes in one direction and a fast eye movement (saccade) in the opposite direction. The function of physiological nystagmus is to return the eyes to the center of the orbit after a slow eye movement. i.

In normal vestibular nystagmus, the slow eye movements are triggered by the vestibular-ocular reflex. The direction is opposite to the direction of head turn. Neural circuitry is shown in Figure 11. ii.

The fast eye movement is in the direction of head rotation (see Nystagmus Worksheet). The neural circuitry underlying the fast eye movements involves vertical and horizontal gaze centers to be discussed in the Eye Movement lecture. b.

Clinically observed nystagmus may involve alternating (or â&#x20AC;&#x153;beatingâ&#x20AC;?) fast and slow movements that are in opposite directions. To describe the direction of nystagmus, report the direction of the fast phase. c.

Spontaneous nystagmus or inappropriate nystagmus are generally signs of damage to the vestibular system or to the cerebellum.

Nystagmus Worksheet. Indicate the directions of fluid movement, slow eye movement, and fast eye movement under condition of a head turn to the left. Figure by Wenstrup.

4.

Other centers can modify or override vestibular reflexes a. cerebellum b. cerebral cortex

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5.

D.

Rotatory and caloric tests diagnose vestibular disorders by activating vestibular reflexes. a.

Rotatory tests examine performance of a functional pair of semicircular canals.

Each functional pair can be tested separately, determined by the orientation of the patientâ&#x20AC;&#x2122;s head relative to the axis of the rotation. b.

Caloric tests examine function of semicircular canals on one side.

Warm or cool water placed in one external auditory meatus evokes characteristic nystagmus Direction: Cool Opposite Warm Same (COWS)

Pathway to Cerebral Cortex (Fig. 12) 1.

Ascending projection forms basis of conscious perception of vestibular stimuli.

2.

Pathway: Lateral, and superior vestibular nuclei ascend bilaterally outside of mlf to the ventroposterior nucleus.

These ascend primarily to areas 3 and 2 of parietal cortex, near somatosensory representation of the, and to the parietoinsular vestibular cortex.

3.

Neurons in these areas often respond to multiple sensory modalities (e.g., proprioceptive and/or visual stimuli). This reflects the multisensory nature of central vestibular processing.

4.

The parietoinsular vestibular cortex appears to be especially important to our sense of self-motion and orientation in space.

Figure 12. Ascending projections from vestibular nuclei to cerebral cortex. Cortical areas 3a, 2v, and parietoinsular vestibular cortex are particularly important recipients of ascending vestibular information. Adapted from Purves et al., Neuroscience 6e, 2018. Fig. 14.12.

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E.

Clinical Issues 1.

Vestibular Signs and Symptoms a.

Spontaneous or inappropriate nystagmus b.

Diminished antigravity reflexes c.

Motion sickness (mismatch between vestibular and visual cues) d.

Vertigo (sensation of spinning: perceived bodily motion)

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V.

FUNCTIONAL PROPERTIES OF THE EAR: TRANSDUCTION OF SOUND ENERGY A.

Aspects of sound 1.

Sound is a propagated disturbance of molecules within a medium (usually air). Periodic stimulus moves air molecules back and forth. This movement causes minute, rhythmic changes in air pressure.

2.

Rate of air pressure change is its frequency, measured as cycles per second or Hertz (Hz). We perceive sound frequency as the pitch of sound. We are sensitive to sounds with vibrations of 20-20,000 Hz. Most mammals are sensitive to frequencies higher than 20,000 Hz, e.g., mice.

3.

Amplitude of the pressure change determines the intensity of sound. We perceive sound intensity as (mostly) loudness of sounds. We hear sounds over a very broad range of sound pressures, about a factor of a million. We use a logarithmic measure, the decibel, to express this broad range of sound pressures that we perceive.

4.

B.

The task of the peripheral auditory system is to convert airborne mechanical waves into electrochemical activity in nerve cells.

Conductive system: conveys mechanical vibration in sound waves to inner ear.

Figure 14. Structure of the human ear. The outer ear includes the pinna, external auditory meatus, and tympanum. The middle ear includes the middle ear ossicles and muscles (not shown), oval and round windows. The cochlea is the auditory structure of the inner ear. Adapted from Purves et al, Neuroscience 6e, 2018, Fig. 13.4.

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1.

The outer ear (Fig. 14) a.

Funnels sound vibrations to middle ear via tympanic membrane. b.

Selectively amplifies some frequencies of sound. c.

Role in locating sound sources.

2.

The middle ear (see Fig. 14) a.

Transmission of sound energy to inner ear. i.

Sound transmitted from tympanic membrane via the middle ear ossicles (the malleus, incus, and stapes) to the oval window. ii.

The net effect of this ossicular chain is to convert airborne vibrations into fluid borne vibrations within the cochlea with little loss of energy. b.

Transmission is controlled by the middle ear muscles.

Contractions increase stiffness of the ossicular chain, mainly attenuating low frequencies. i.

Stapedius muscle innervated by facial nerve. ii.

Tensor tympani muscle innervated by trigeminal nerve.

3.

Pathologies of conductive system (= conductive hearing loss). a.

Blockage of external ear canal. b.

Perforation or rupture of tympanic membrane. c.

Middle ear i. otitis media ii. otosclerosis d.

Disruption of conductive system reduces sensitivity by as much as 30 decibels for lower frequencies, and is more severe at higher frequencies. e.

Paralysis of middle ear muscles can distort sound conduction through middle ear.

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C. Sensorineural system: The cochlea transduces sound, analyzes sound frequency, and controls the sensitivity of transduction and frequency analysis (see Fig. 15)

Figure 15. A. The cochlea, part of the inner ear, consists of three fluid-filled tubes that extend throughout its entire length of ~ 35 mm. B. Cross section of cochlea shows arrangement of the three tubes. The oval window, against which the stapes pushes in response to sound, communicates with the scala vestibuli. The scala tympani is closed at its base by the round window, a thin, flexible membrane.

Between these two compartments lies the scala media, an endolymph-filled tube whose epithelial lining includes the hair cells resting on the basilar membrane. The organ of Corti contains, in addition to many support cells, two types of receptors cells called hair cells. Taken from Purves et al., Neuroscience 6e, 2018, Fig. 13.5.

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1.

Anatomy of sound transduction a. b.

c.

d.

e.

f.

Cochlea is a long, coiled tube (~35 mm, ~2.5 turns) extending from the base to the apex There are three fluid compartments in the cochlea i.

Scala vestibuli -opening to oval window -contains perilymph (~0 mV) ii.

Scala media -separated by Reissner â&#x20AC;&#x2DC;s (=cochlear duct) membrane from scala vestibuli -contains endolymph generated by stria vascularis -endolymphatic potential in scala media = ~+80 mV iii.

Scala tympani -separated by basilar membrane from scala media -connected to scala vestibuli at the helicotrema (at apex of the cochlea) -borders the round window -contains perilymph Basilar membrane i.

Runs length of cochlea ii.

Separates scala media and scala tympani iii.

Sensory organ (organ of Corti) rests on basilar membrane Organ of Corti i.

Contains sensory hair cells and various supporting cells ii In each cross-section, 1 inner hair cell and 3 outer hair cells iii.

Hair cell stereocilia project in endolymph of scala media, contacting tectorial membrane.

There are two types of auditory hair cells (Fig. 15) i.

Inner hair cells --Make contact with 95% of auditory nerve fibers --Supply most of auditory information from cochlea to CNS ii.

Outer hair cells --Contact only ~5% of auditory nerve fibers ii.

--Regulate cochlear tuning and sensitivity of inner hair cells Tectorial membrane i.

Runs the length of the cochlea, lying directly over the hair cells ii.

Stereocilia of outer hair cells embed into the tectorial membrane iii.

Stereocilia of inner hair cells lie free, just below tectorial membrane

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2.

Mechanism of Sound Transduction: activation of hair cells (Fig. 16). a.

Transduction depends on transmission of sound energy from middle ear to inner ear. i Pressure applied by stapes at oval window increases pressure in scala vestibuli. ii.

This pressure wave causes vibration of the basilar membrane, which activates hair cells.

Figure 16. Top: Transmission of mechanical vibrations in sound from external auditory meatus into the cochlea. Adapted from Felten and Jozefowicz, Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, 2003, Fig. III.14.

Bottom: Another view of motion along the basilar membrane. Adapted from Purves et al., Neuroscience 6e, 2018, Fig. 13.6

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b. c. d.

e.

Mechanism of hair cell activation is very similar to vestibular hair cells.

Motion of basilar membrane in response to sound causes hair cells to move relative to the endolymph (inner hair cells) or relative to tectorial membrane (outer hair cells). (Fig. 17) Deflection of hair cell stereocilia in one direction increases potassium influx, depolarizing hair cell. Deflection in other direction reduces potassium influx below resting levels, hyperpolarizing cells.

Depolarized hair cells release excitatory neurotransmitter onto distal processes of auditory nerve fibers, causing them to discharge action potentials.

Figure 17. Vertical movement of the basilar membrane is translated into a shearing force that deflects the sterociliary bundles of the hair cells. The deflection of the stereocilia in the upward phase opens potassium channels, allowing potassium to enter and depolarize hair cells. The downward deflection of the basilar membrane closes channels and hyperpolarizes the hair cell. Taken from Purves et al., Neuroscience 6e, 2018, Fig. 13.7.

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3.

Frequency analysis (see Fig. 18) a.

b.

c.

d.

The Traveling Wave: Pressure applied by stapes at oval window increases pressure in scala vestibuli. This pressure wave causes vibration of the basilar membrane. This vibration moves along the basilar membrane from base to apex as a Traveling Wave.

The greatest vibration of the basilar membrane occurs at one position along its length, determined by the frequency of the sound. High frequencies cause the point of maximum deflection to be close to the base.

Systematic change in stiffness of basilar membrane is a crucial feature of cochlea's response to sound. The basilar membrane is stiff near its base (near the oval window) and becomes less stiff toward the apex. As a result, high frequency sounds cause maximum vibration at the stiffer, basal end of the basilar membrane. Low frequencies cause maximum vibration at the floppier, apical end.

Due to this frequency sensitivity of the basilar membrane response, hair cells nearer the base respond maximally to high frequency sounds, while hair cells nearer the apex respond maximally to lower frequency sounds. The basilar membrane is said to be tonotopically organized, i.e., organized by the frequency of sound that maximally stimulates its different parts.

Figure 18. Schematic diagram of the cochlea showing how sound pressure waves travel from base to apex. Different frequencies of sound cause maximum vibration at different places along the basilar membrane. The graphs on the right indicate the location of maximum amplitude of vibration. Taken from Purves et al., Neuroscience 6e, 2018, Fig. 13.6

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4.

Roles of inner and outer hair cells a. b.

c.

The function of inner hair cells is to provide information to the central nervous system. Each inner hair cell receives synaptic contacts from about 10-20 auditory nerve fibers.

The primary function of outer hair cells is to regulate the motion of the basilar and tectorial membranes. i.

Outer hair cells provide very little direct information to central nervous system, yet they are essential for full sensitivity and frequency tuning of inner hair cells. ii.

Outer hair cells transduce sound in the much the same way as inner hair cells iii.

Outer hair cells are contractile: they shorten with each sound-induced depolarization. Because they are connected to both basilar and tectorial membranes, their contraction and relaxation greatly amplifies the vibration of the basilar membrane. The largest amplification occurs at the point on the basilar membrane where the vibration is largest. iv.

Outer hair cells are particularly susceptible to noise damage and to aminoglycoside antibiotics. These can cause significant loss of hearing sensitivity and frequency selectivity due to the death of outer hair cells.

Modulation by efferent innervation i.

The contraction of outer hair cells is modified by efferent neurons that synapse onto these outer hair cells. ii.

Activation of these efferent neurons appears to play two roles -Allows the cochlea to cancel out the effect of background noise -Protects the cochlea from damage in the presence of loud sounds iii.

These efferents are called â&#x20AC;&#x153;olivo-cochlearâ&#x20AC;? efferents because they originate in a brainstem nucleus called the superior olivary complex.

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VI.

THE AUDITORY SYSTEM A.

General overview: System-wide features 1.

Complex arrangement of fiber bundles and nuclei. a.

Crossed and uncrossed components b.

Why the complexity? Brainstem nuclei create different auditory response properties. Higher centers integrate these different responses to fully represent auditory stimuli.

2.

What is the order within this complexity? a.

Systematic representation of the frequency of sounds (= tonotopic organization) within the cochlea and each of the ascending auditory nuclei through primary auditory cortex (area 41). This organization is based on two features: i. auditory hair cells are responsive to particular frequencies of sound, due to their location on the basilar membrane (Fig. 19). ii. the highly organized connection from the hair cells to auditory nerve fibers to the auditory brainstem nuclei. This connection preserves the cochlear frequency organization throughout the brain.

Figure 19. Auditory neurons are sharply tuned in different frequencies of sounds because they connect to hair cells located on a particular part of the basilar membrane.

Diagram shows correspondence of cochlear vibration pattern and frequency tuning of hair cells and the auditory neurons to which they are connected. From Purves et al., Neuroscience 6e, 2018, Fig. 13.12.

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b. c. d.

B.

Representation of contralateral sound field in the inferior colliculus and higher levels.

Brainstem inputs converge on inferior colliculus to fully represent sound.

Other response properties, such as cues for sound localization, may also be systematically represented.

Ascending auditory pathway (Fig. 20)

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Figure 20. Ascending auditory pathway. Adapted from Purves et al., Neuroscience 6e, 2018, Fig. 13.13.

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1.

Auditory Nerve: Fibers of neurons in spiral ganglion project to the ipsilateral cochlear nucleus. a.

Each fiber contacts a single inner hair cell b.

Each fiber terminates in each of the subdivisions of the cochlear nucleus (dorsal and ventral cochlear nucleus)

2.

Cochlear nucleus: Dorsal (DCN) and ventral (VCN) a.

Input from ipsilateral auditory nerve b.

Tonotopic organization in each of the cochlear nuclei. c.

Dorsal and ventral nuclei differ in responses â&#x20AC;˘ VCN analyzes timing of sounds â&#x20AC;˘ DCN analyzes vertical sound location

3.

Axons leave the cochlear nuclei by way of several fiber tracts (acoustic striae). Most of these axons cross the midline. The largest group of these axons crosses the midline in the Trapezoid Body.

4.

Superior olivary complex (SO) a.

Principal nuclei of the SO are the first stage in the ascending auditory pathway to compare information from the two ears. These SO neurons analyze either time differences in the arrival of sounds at the two ears, or intensity differences in sounds arriving at the two ears. BOTH are important cues for locating a sound source in space. b.

Accessory nuclei project to cochlear nuclei and to the cochlea.

The olivo-cochlear pathway modulates cochlear function.

5.

Lateral lemniscus is composed of fibers projecting to the inferior colliculus a.

Origin of fibers is in superior olivary complex and cochlear nuclei b.

Many of the fibers from the cochlear nucleus and superior olivary complex have CROSSED THE MIDLINE by the time they enter the lateral lemniscus. As a result, most of these lateral lemniscal neurons convey information about sounds presented to the contralateral ear.

6.

Inferior colliculus (IC) a.

Is tonotopically organized, so that it systematically represents the frequency of sounds. b.

Receives converging ascending input from all lower auditory nuclei. A major function is to integrate information from all the brainstem auditory centers. c.

Most neurons respond best to stimulation of the contralateral ear, although some neurons also respond to stimulation of the ipsilateral ear. The contralateral ear dominance is the result of the predominantly CROSSED projections from auditory brainstem neurons as their axons ascend to the IC. i.

The result of this contralateral ear dominance is that the IC and higher auditory centers represent and analyze sounds in the CONTRALATERAL SOUND FIELD. ii.

When one of these higher auditory centers is lesioned 29

Winters Vestibular and Auditory Systems

unilaterally, there is a deficit in the ability to locate and analyze sounds in the sound field contralateral to the lesion.

7.

Brachium of the inferior colliculus is composed of fibers of IC neurons projecting to medial geniculate nucleus.

8.

Medial geniculate nucleus (MGN) of the thalamus a.

Receives ascending inputs from IC (mostly ipsilateral) via brachium of inferior colliculus. b.

It projects to several areas of auditory cortex c.

Serves as gateway to auditory cortex: Descending input from auditory cortex modifies activity of MGB neurons.

9.

Auditory radiation (part of the internal capsule) is the fiber pathway from MGB to auditory cortex.

10.

Primary Auditory cortex (in Transverse temporal gyrus) a.

Location on the superior surface of the superior temporal gyrus of the temporal lobe, buried within the lateral sulcus (Fig. 21). b.

Area 41 is the primary auditory cortex, organized tonotopically.

Low frequency sounds are analyzed rostro-laterally, and high frequency sounds analyzed caudo-medially. c.

Primary auditory cortex analyzes complex features of sound: the frequency content of sounds, temporal patterns, cues used in localizing sounds, speech patterns.

Figure 21. Human auditory cortex is located in the transverse temporal gyrus of Heschl. Blue indicates primary auditory cortex; pink indicates secondary auditory cortex. From Purves et al.

Neuroscience 6e 2018, Fig. 13.16.

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11.

Effects of central lesions. a.

Unilateral lesions of the cochlea, auditory nerve, and cochlear nuclei cause deafness or impaired hearing in one ear. b.

Unilateral lesions above SOC do not result in unilateral deafness because information from both ears ascends on each side of the brain. However, hearing is impaired, particularly the ability to locate and analyze sounds in the contralateral sound field.

12.

Beyond primary auditory cortex (Fig. 21) a.

Association auditory cortex includes areas 42 (on transverse temporal gyrus) and 22 (superior temporal gyrus). b.

These areas appear to perform more specialized analyses of sounds, receiving input from primary auditory cortex. i.

Some association cortex may analyze sound location cues ii.

The posterior part of area 22 in the left cerebral cortex appears specialized for speech processing. This area in the left cerebral cortex is called Wernickeâ&#x20AC;&#x2122;s area. Occlusion of branches of the middle cerebral artery can damage this area, impairing language comprehension while leaving analyses of non-speech sounds unaffected.

13.

Descending pathways a.

Olivo-cochlear pathways: modulation of cochlear function through synapses onto inner and outer hair cells. Two functional roles: i.

Allows the cochlea to cancel out the effect of background noise ii.

Protects the cochlea from damage in the presence of loud sounds b.

Descending projections from auditory cortex to auditory thalamus, midbrain, and brainstem. Basis for modulation of ascending input.

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C.

Clinical Issues 1.

Signs and symptoms a.

Hearing loss: temporary or permanent b.

Tinnitus: perception of sound when there is no sound. c.

Impairments of speech comprehension d.

Psychological disorders resulting from hearing loss

2.

Hearing disorders can result from: a. age- (presbycusis) b. use (e.g., exposure to noise or loud sounds) c. pathological processes (e.g. tumors, vascular accidents, genetic defects) d. toxic substances, e.g., aminoglycoside antibiotics, chemotherapuetuic agents

3.

General types of hearing dysfunction a.

Conductive loss: vibrations associated with sound are not properly conducted (mechanically) into the inner ear. Results from disorders in the outer or middle ear (e.g. otitis media, otosclerosis). b.

Sensorineural loss: vibrations in the inner ear are not properly converted into electrical potentials or are not transmitted into the central nervous system. Results from disorders of hair cells or auditory nerve: i.

Moderate sound exposure that causes a temporary hearing loss can cause permanent elimination of synapse of inner hair cell onto auditory nerve fiber: no loss of hearing â&#x20AC;&#x153;sensitivityâ&#x20AC;? in standard measurements but reduced ability to hear complex sounds, like speech in background noise ii. more severe sound exposure causes loss of hair cells that results in permanent loss of hearing sensitivity, as well as reduced ability to hear complex sounds iii. other conditions (e.g., genetics, age, disease, ototoxic substances) can lead to loss of hair cells. c.

Central: interruption or alteration of ascending auditory pathways can result in hearing loss and/or tinnitus. i.

Causes include tumors, cardiovascular accidents, and agerelated changes. ii.

Central changes can result from conductive or sensorineural hearing loss. iii.

Moderate hearing loss results in social isolation and psychiatric disorders including depression.

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4.

Clinical tests a.

Audiometry b.

Simple screening tests (Fig. 22.) i.

Rinne ‘s test (threshold by air/bone conduction) ii.

Weber ‘s test (lateralization test) c.

Sophisticated clinical test, e.g., auditory evoked potentials (Fig. 23).

Figure 23. Auditory brainstem responses (ABR) obtained in

Figure 22. Simple clinical tests for hearing.

From Greenberg et al: Clinical Neurology; www.accessmedicine.com response to repeated brief sounds.

Each peak represents the activity of many neurons, usually within a particular anatomical region. For instance, peak “I” is thought to represent activity in the auditory nerve. Loss or delay of these peaks can help diagnose type of hearing loss. The ABR in response to sound in the right ear indicates a pathology between the auditory nerve and the auditory brainstem. This is consistent with a vestibular schwannoma (“acoustic neuroma”).

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Image Acknowledgments Greenberg DA, Aminoff MJ, Simon RP: Clinical Neurology; www.accessmedicine.com. McGrawHill.

Felten, D.L. and Jozefowicz, R. (2003), Netterâ&#x20AC;&#x2122;s Atlas of Human Neuroscience, Icon Learning Systems.

Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, Mooney RD, Platt ML, White LE (2018) Neuroscience 6e. Sunderland, MA: Oxford University Press, New York.

Squire, L., Berg, D., Bloom, F., du Lac, S., Ghosh, A., Spitzer, N. (2008) Fundamental Neuroscience. Academic Press.

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Pain and Pain Mechanisms Merri Rosen, Ph.D. LEARNING OBJECTIVES:

1.

Describe the location and structure of nociceptors

2.

Describe the transduction of nociceptive signals

3.

Describe the mechanisms that induce the following categories of pain: nociceptive, inflammatory, and neuropathic/neuroimmune pain

4.

Distinguish chronic and acute pain, and their underlying mechanisms

5.

Describe phantom limbs and phantom pain, and the underlying mechanisms

6.

Distinguish between referred and non-referred visceral pain, and explain how each are conveyed

7.

Describe the gate theory of pain and how it works

8.

Describe where and how opioids and cannabanoids exert their effects

9.

Explain how pain hypersensitivity arises

10. Describe peripheral targets for pharmacological pain treatment 11. Describe and distinguish the following elements that contribute to central pain sensitization: windup, allodynia, and transcription 12. Define and explain the following Key Words: Allodynia Anterolateral system Ad and C fiber nociceptor Ad mechanosensitive nociceptor Ad mechanothermal nociceptor Capsaicin Central sensitization Dorsolateral tract of Lissauer Dynorphin Endogenous opioid Endorphin Enkephalin First pain Gate theory of pain

Hyperalgesia Neuropathic pain Nociception Nociceptor Pain tolerance Pain threshold Peripheral sensitization Placebo effect Polymodal nociceptor Second pain Sensory discriminative Spinothalamic tract (STT) TRP channel Vanilloid receptor

Required reading: Chapter 10, Neuroscience 6th Edition, Purves (ed), Sinauer Press, 2017.

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PAIN Overview Pain is a sensation. Sensations that are intense, unpleasant, or distressing are described as being painful.

Pain is not homogeneous, but falls into three general categories: (a) Physiological pain (nociception) (b) Inflammatory pain (inflammation) (c) Neuropathic/neuroimmune pain (pathological) Multiple mechanisms contribute to the sensation of pain. Pain is subject to various types of modulation, which can take place at the level of pain receptors in the periphery, in signal transduction mechanisms, and in anatomical pathways in the peripheral and central nervous systems.

Clinical Significance Pain alerts the brain to the presence of noxious or potentially threatening stimuli. Pain threshold, which is the minimum stimulus that elicits pain, is an indication of the health of the receptors, nerves, and pathways in the pain system. Pain tolerance, which is the degree of pain a subject can tolerate before experiencing physical or emotional impairment, may be altered by medications as well as by physical, cognitive and affective interventions and training. Pain hypersensitivity, a pathological condition arising from changes in signal transduction in the peripheral or central nervous system, can cause great emotional distress.

NOCICEPTION General principles of nociception Nociceptors (pain receptors), like other somatic sensory receptors, arise from cell bodies in dorsal root ganglia (or in the trigeminal ganglion), and send one axonal process to the periphery and the other into the spinal cord or brainstem.

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(A) The cell bodies of pain afferent fibers reside in a series of dorsal root ganglia (DRG) along the spinal cord or in the trigeminal ganglia.

(B) Pseudo-unipolar neurons in the DRG give rise to a peripheral branch of the pain nerve fiber that ramifies within the skin or muscle.

Afferents carrying pain and temperature information terminate as free endings. The second branch of the pseudo-unipolar neuron gives rise to a central process that synapses with neurons in the spinal cord or brainstem.

Peripheral nociceptive axons terminate in unspecialized â&#x20AC;&#x153;free endingsâ&#x20AC;?, in contrast to other somatic sensory receptors (e.g. Pacinian corpuscles etc).

DRG

Spinal cord

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What is pain NOT? Pain is not an excessive stimulation of the same receptors that generate the other somatic sensations. Pain perception uses specific receptors and pathways.

Nociceptors that transduce thermal stimuli respond at high temperatures that can induce tissue damage. These are distinct from non-nociceptive thermoreceptors, which transduce thermal stimuli that don’t cause a sensation of pain, such as low levels of heat or cold that don’t cause tissue damage (non-noxious stimuli). Thermoreceptor and nociceptor response ranges have little overlap.

Number of fibers

• Nociceptor axons conduct relatively Mixed nerve C (IV) Nociceptor, Thermal Receptors slowly, are either only lightly A (III) Nociceptor, Thermal Receptors myelinated, or are unmyelinated.

• Nociceptors are characterized A (II) according to the properties of axons associated with them: A (I) (a) Ad group of myelinated axons (also called Group III fibers): conduction velocity 5-30 m/s; respond to dangerously intense mechanical or thermal stimuli. (b) C-fiber group of unmyelinated axons (also called Group IV fibers): 0 2 4 6 8 10 12 14 16 18 conduction velocity < 2 m/s; 0 36 72 108 m/sec respond to thermal, mechanical and chemical stimuli – referred to as polymodal.

Thus, there are fast (5-30 m/s) and slow (< 2 m/s) pain pathways.

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Two categories of pain perception: sharp first pain and dull second pain.

A noxious stimulus first activates the large diameter Ad fibers, giving rise to a sharp first pain. If the stimulus intensity is increased, then the unmyelinated smaller diameter Cfibers are activated, giving rise to a slower, more delayed second pain (panel A below). If the Ad or C fibers are selectively anesthetized, a stimulus will cause either a sharp pain or a dull pain, but not both (panels B and C below).

Classification and distribution of nociceptors Nociceptors can be classified according to their responsiveness to diferent stimuli: â&#x20AC;˘ mechanonociceptors are activated by mechanical tissue damage â&#x20AC;˘ thermonociceptors are activated by tissue damage caused by heat or cold â&#x20AC;˘ chemonociceptors are activated by tissue damage caused by chemicals Nociceptors are found in the skin, muscles, joints and visceral organs, and mediate pain in each of these regions. Nociceptors in joints mediate joint pain due to conditions such as arthritis, for example, while pain receptors in the heart may be activated by ischemia.

The density of free nerve endings at the peripheral end of a nociceptive neuron can vary in different regions of the body and contribute to different pain intensities.

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Pain Mechanisms Rosen

Transduction of nociceptive signals – the vanilloid receptor Vanilloid receptors: (VR receptors) (1) Most VR receptors are sensitive to both heat and capsaicin, the ingredient in chili peppers that causes the burning or tingling sensation produced by spicy foods.

Since the receptor is sensitive to both capsaicin and heat, peppers seem “hot”.

(2) Some VR receptors are sensitive only to heat and not to capsaicin. Others are activated by acids (H+).

(3) VR receptors are found in C and Ad fibers (on their free nerve endings).

(4) Different VR receptors are activated by different heat levels: the VR-1 receptor is activated by moderate heat (45oC) that is considered uncomfortable, while the VRL-1 receptor has a higher heat threshold (52oC).

(5) VR receptors are members of the TRP (transient receptor potential) family: many other somatosensory receptors also belong to the TRP family.

(6) Transduction by nociceptors is similar to those by other somatosensory receptors, except that the triggers for activating nociceptors can be different. Under resting conditions, the pore of the VR receptor channel is closed. When activated by capsaicin or high heat, the channel opens, allows an influx of sodium and calcium ions, depolarizes the membrane of the nociceptor cell, and causes action potentials to be generated in the nociceptor fibers – i.e. the Ad or C nerve axons.

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PAIN CATEGORIES Physiological / Nociceptive pain • Acute pain, via direct activation of nociceptors (damage to the nerve terminals without the release of secondary chemicals).

Inflammatory pain • Re-activation of nociceptors via substances released by tissue damage Peripheral nerve endings on pain fibers (e.g. in the skin) are activated by different chemicals that are released following tissue damage. Tissue damage releases bradykinin, prostaglandins, serotonin (5-HT), etc, which activate nociceptors. Nociceptor activation leads to the release of substance P and CGRP (calcitonin gene related peptide) from the nociceptor nerve endings. Substance P acts on mast cells which release histamines which directly re-activates nociceptors. Re-activation helps protect the site from further injury (as a result of pain from both the injured site and from ordinary stimuli near site of damage – see below for Pain Sensitization). CGRP and substance P dilate blood vessels which causes inflammation. The activation of mast cells and blood vessels also promotes healing and guards against infection by increased blood flow and migration of white blood cells to the site.

Inflammatory response to tissue damage

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Neuropathic pain: Pathological pain caused by damage to, or malfunction of, the nervous system. Neuropathic pain is a chronic pain syndrome.

Neuropathic pain is pain initiated or caused by a primary lesion or dysfunction in the PNS or CNS. Most common neuropathic symptoms include allodynia and hyperalgesia, or pain evoked by a normally non-painful stimulus and exaggerated pain evoked by normally moderately painful stimulus, respectively. Neuropathic pain is usually chronic, and can exceed six months. Neuropathic pain can be accompanied by hyper-responsiveness to applied stimuli, and nerve sprouting, which results in structural remodeling and anatomical reorganization of neuronal circuitry. Sprouting can occur at the peripheral injury site or remotely in the DRG and spinal cord.

• Sprouting AB fibers can contact nociceptive fibers and directly active them

Here, the spinothalamic tract (STT) ascends towards the VPL nucleus of the thalamus.

Peripheral nerve injury leads to: ® local neuroinflammation ® local invasion of immune cells that become activated ® increased levels of proinflammatory molecules released from damaged tissue, immune cells, peripheral glia, and central glia • proinflammatory molecules can be sprouting factors o trigger sympathetic sprouting from neighboring sympathetic ganglia (SG) o trigger sprouting of large myelinated Aβ into superfical laminae of the dorsal horn • proinflammatory molecules also mediate the transition of neuronal activity from normal to hyperresponsiveness, in response to peripheral stimulation ® Immune cells also invade the DRG and the dorsal horn of the spinal cord ®® Sprouting and neuronal sensitization, controlled by remote neuroimmune signaling, contribute to an abnormal sensation of pain interpreted by the cerebral cortex (Cc).

(Saab & Hains (2009), Trends in Neurosciences 32(2), 110-117)

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Neuropathic pain 2: Neuroimmune pain Immune responses can contribute to neuropathic pain.

After spinal cord injury (SCI in figure), changes below the lesion cause neuroimmune signaling remote from the primary injury site. (Illustrated with a thoracic lesion.)

Immune signaling below the injury site ® • Microglial induced inflammation in dorsal horn ® • Affects nociceptive relay neurons (second order) in spinal cord dorsal horn ® • Inflammatory signal from dorsal horn to thalamus (VPL) ® • Hyperactivity of microglia in thalamic VPL neurons ® • Increased inflammation in thalamus ® • Increased pain perception in cortex.

CCL21 (Chemokine ligand 21) and PGE2 (prostaglandin E2) are inflammatory molecules; Micr = resting microglia; Mica = active microglia; SCI = Spinal cord injury (Saab & Hains (2009), Trends in Neurosciences 32(2), 110-117)

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CHRONIC PAIN and ACUTE PAIN Chronic pain is pain that lasts for longer than several months (the actual time varies in different definitions of chronic pain, but itâ&#x20AC;&#x2122;s usually pain that lasts for longer than 3-6 months). Acute pain is sometimes defined as pain that lasts for up to ~30 days.

Chronic pain can be nociceptive or neuropathic/neuroimmune pain.

Acute pain is most likely mainly nociceptive.

Phantom Pain The loss of a limb generates an internal mismatch between the brainâ&#x20AC;&#x2122;s representation of the body and the pattern of peripheral input that reaches the neocortex. The consequence is the illusion that the missing body part is still present and functional. The phantom sensation occurs almost immediately after limb loss and decreases with time. Amputees can sometimes develop phantom pain, which they ascribe to the missing limb. Phantom pain can develop from a functional re-organization of the cortex following damage to the nociceptors that occurs following limb loss (the phantom is indicated by a dashed line with the colored regions showing the most vividly experienced parts).

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Mechanisms of phantom pain Nociceptors can cause chronic pain if they are damaged. (A) In the normal state, if a nociceptor is activated by a noxious stimulus, the nerve cell transmits the information via the sensory system to create a painful sensation in the brain. (B) If the nociceptor is damaged due to limb loss, it can start firing randomly and activate other nerves that eventually cause phantom pain, due to cortical reorganization.

Illustration by M. Rosen

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VISCERAL PAIN â&#x20AC;&#x201C; Non-Referred There is a recently-described pain pathway that conveys visceral nociception. This is visceral pain that is non-referred.

This pathway is relevant because it allows a midline myelotomy to be a sometimes effective therapy for visceral pains such as arise from cancers. See the Somatosensory Pathway lecture for detailed information.

Pathway for visceral pain, a component of the DC/ML system.

Purves Box 10C.

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REFERRED PAIN (VISCERAL) There are few dorsal horn neurons in the spinal cord that are specialized solely for visceral pain. Visceral pain is conveyed centrally via dorsal horn neurons that are also concerned with cutaneous pain. As a result, pain in an internal organ is sometimes perceived as cutaneous pain. This is called referred pain. E.g. angina pain (heart wall) referred to the upper chest wall and radiating to the left arm.

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The Gate Control theory of pain The gate control theory of pain, put forward by Ron Melzack and Patrick Wall in 1962, is the idea that physical pain is not simply a direct result of activation of pain receptor neurons, but that its perception is modulated by interaction between different neurons.

The interplay among these connections determines when painful stimuli go to the brain. â&#x20AC;˘

When no nociceptive or mechanoreceptive input comes in: The inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed). No pain.

â&#x20AC;˘

When there is more mechanoreceptive input than nociceptive: Both the inhibitory neuron and the projection neuron are stimulated, but the inhibitory neuron prevents the projection neuron from sending signals to the brain (gate is closed). Diminishes/eliminates pain perception. o Also occurs via activation of descending pathways from the brain, in the place of mechanoreceptor activation.

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When there is more nociceptor input than mechanoreceptor: This inactivates the inhibitory neuron, and the projection neuron sends signals to the brain informing it of pain (gate is open).

Illustration by M. Rosen

This theory doesn't tell us everything about pain perception, but it does explain some things. If you rub or shake your hand after you bang your finger, you stimulate normal somatosensory input to the projection neurons. This closes the gate and reduces the perception of pain. (Trends in Neurosciences Vol 32, Issue 2, February 2009).

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DESCENDING CONTROL OF PAIN (Gate Control of Pain) Descending systems can modulate the perception of pain based on attention, distraction, and expectation. For example, soldiers have reported relatively little pain after receiving a serious wound. This may relate to high stress levels that are coupled with the recognition that a wound might allow them to leave the battlefield. Also, pain perception thresholds tend to be higher than average in "rough" occupations such as coal mining.

• The descending systems that modulate pain originate in the somatosensory cortex, the hypothalamus, the periaqueductal gray matter of the midbrain, the raphe nuclei, and other nuclei of the rostral ventral medulla. Modulation of pain occurs at each of these sites as well as in the dorsal horn.

• Activation of mechanoreceptors modulates the transmission of nociceptive information to higher centers (gate control of pain).

• Enkephalin containing local circuit neurons exert descending control on nociceptive signal transmission.

Purves et al., Neuroscience, 2017. Fig 10.8

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CENTRAL SENSITIZATION OF PAIN (Pain Hypersensitivity) Neural plasticity in the somatosensory system produces pain hypersensitivity. There are several mechanisms that can contribute to central pain sensitization.

Central pain sensitization: Windup • • • •

Windup

Immediate onset, activity dependent, and transcription independent.

Lasts only during nociceptive stimulation Percept: Repeated identical stimuli, pain increases with each stimulus Due to summation of slow synaptic potentials in dorsal horn neurons o activation of voltage-dependent Ltype Ca2+ channels o release of Mg2+ block of NMDA receptors

Recording from dorsal horn neuron

C fiber activation Ji et al (2003), Trends in Neurosciences, 26(12), 696-705.

Allodynia

Central pain sensitization: Allodynia Allodynia: Induction of pain by normally innocuous stimulus • Immediate onset, activity dependent, and transcription independent.

• Outlasts pain by hours • Percept: light touch causes pain • • •

Heterosynaptic: convergent inputs of nociceptive inputs and cutaneous inputs onto dorsal horn neurons Ab fiber activation (light touch) that is normally subthreshold now activates dorsal horn neurons (see Allodynia figure) Involves LTP (long term potentiation) of dorsal horn neurons

Recording from dorsal horn neuron

Ab fiber activation C fiber activation Ji et al (2003), Trends in Neurosciences, 26(12), 696-70.

Modified from Purves 10.8C

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Central pain sensitization: transcription-dependent Transcription of components that increase neural excitability • Late onset, activity independent, and transcription dependent.

• Later onset, long-lasting • Percept: light touch causes pain Example: • Microglia and astrocytes ® • Transcription of COX-2 enzyme (COX is an enzyme in biosynthesis of prostaglandins in both periphery and dorsal horn) ® • Prostaglandin production in periphery and dorsal horn neurons ® • Increased neural excitability •

Can be treated with COX inhibitors o COX inhibitors affect both dorsal horn and periphery

Purves et al., Neuroscience, 2017. Fig 10.7

Peripheral targets for pain treatment Within the periphery, nociceptor activation elicits a cascade of responses as outlined above under Inflammatory Pain. There are several targets for pain treatment in this region.

• NSAIDs (nonsteroidal anti-inflammatory drugs) – aspirin, ibuprofen o Inhibit COX (cyclooxygenase) – enzyme in biosynthesis of prostaglandins • Block TNFa with antibody o Treat autoimmune / inflammatory diseases such as rheumatoid arthritis • Block NGF with antibody o Reduce hyperalgesia (still under research, has been tested only in animal models)

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OPIATE and CANNABINOID CONTROL OF PAIN Opium derivatives such as morphine are known to be analgesics. Brain regions sensitive to opioid drugs also produce analgesia when directly stimulated, suggesting the existence of endogenous opiods. Opiates act on most or all sites involved in the descending control of pain.

CNS regions susceptible to opiate drugs include most of the central sites in the figure below, particularly the periaqueductal gray matter and opiate-sensitive neurons in the dorsal horn of the spinal cord.

Endogenous opioids include enkephalins, endorphins and dynorphin. All three are found in the periaqueductal gray matter. Enkephalins and Purves et al., Neuroscience, 2017. Fig 10.8 dynorphins are also present in the rostral ventral medulla and in spinal cord regions. Enkephalin-containing local circuit neurons in the dorsal horn synapse with axon terminals of nociceptive afferents, which in turn synapse on dorsal horn projection neurons (see Figure on Page 15). The release of enkephalin onto nociceptive terminals inhibits the release of transmitter from these terminals onto the projection neuron. This reduces the amount of activity traveling to higher CNS centers.

Cannabinoids also can modulate pain. The analgesic effects of marijuana led to the discovery of endocannabinoids.

Cannabanoids suppress nociceptive neurons in the dorsal horn, and endocannabanoids modulate neural excitability in the CNS.

THE PLACEBO EFFECT The placebo effect is defined as a physiological response following the administration of a pharmacologically inert remedy. E.g. in a study conducted on medical students given either a “sedative” or a “stimulant” (in fact they are both just sugar pills), more than half the number receiving the “sedative” reported feeling drowsy and a high percentage of students receiving the stimulant reported feeling less tired. Or, in another study, 75% of patients suffering from post-operative wound pain report feeling relief after injection of sterile saline. The placebo effect can be blocked by naloxone, which is a competitive antagonist of opiate receptors (i.e., it binds to opiate receptors, thus preventing binding of opiates themselves to the receptors). Imaging studies show that placebo administration activates endogenous opiate receptors in cortical and subcortical pain-related regions.

The placebo effect thus has a physiological basis, so the effects on pain perception are real, and are presumably due to descending control of pain. The effectiveness of a placebo does not diminish the real-ness or seriousness of an individual’s pain.

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Image Acknowledgments: Purves D, Augustine GJ, Fitzpatrick D, Hall WC, LaMantia A-S, Mooney RD, Platt ML and White LE (2017) Neuroscience, Sixth Edition. Sunderland, MA: Sinauer Associates.

Additional images by S. Sivaramakrishnan and M. Rosen.

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